TW200824682A - Therapeutic and/or preventive agent for intraocular disorder comprising statin compound - Google Patents

Abstract

An object of the present invention is to provide an agent for inhibiting DNA synthesis of retinal vascular endothelial cells, and agents for treatment and prevention of intraocular disorders. The present invention is essentially based on an example that a fat soluble statin compound inhibits DNA synthesis of retinal vascular endothelial cells, and inhibits cell proliferation, and relates to a therapeutic agent or a preventive agent for intraocular disorder which contains a statin compound as an active ingredient. Namely, the above-mentioned problem is solved by an agent for inhibiting DNA synthesis of retinal vascular endothelial cells, an agent for treatment or prevention of intraocular disorders containing a statin compound as an active ingredient.

Description

[Technical Field] The present invention relates to a treatment, a preventive agent, and the like for an intraocular disease containing a Statin compound as an active ingredient. In more detail, the present invention relates to an intraocular disease which contains a history compound as an active ingredient and has proliferation inhibition, contraction inhibition, anti-inflammatory, anti-oxidative or neuroprotective effects on intraocular cells. Treatment preventive agents, etc. [Prior Art] The present application claims the priority application based on Japanese Patent Application No. 2006-279338 and No. 2007-65927, the contents of which are incorporated herein by reference. . For senile macular degeneration (exudative, atrophic), diabetic retinopathy, traction retinal detachment, vitreous A, macular edema, retinopathy of prematurity, uveitis, allergic conjunctivitis, spring conjunctivitis, and glaucoma The disease 'is still lacking effective therapeutic or prophylactic agents. Therefore, the industry is looking forward to the development of a drug that can effectively prevent or treat such diseases. The Styda compound also contains a lactone type which is a precursor drug and becomes an acid form in a living body. Further, the acid-type statin compounds each have 3,5-hydroxy valeric acid (DHVA) and other hydrophobic portions. A structure similar to DHVA can be seen in the matrix of HMG-C〇l reductase and its reaction intermediate. Therefore, the statin compounds all exert the function of hmg_reductase to inhibit sodium. Further, the Statin compound is widely known as a therapeutic or preventive agent for hyperlipidemia. 312XP/Inventive Manual (Supplement)/97-01/96138443 6 200824682 In the patent publication No. 2003-511347 (hereinafter referred to as Patent Document 1), there is disclosed an invention entitled "Use of HMG - CoA Reductase Inhibitory Substance" The invention of up-regulating endothelial cell nitric oxide synthase. Specifically, it is disclosed in the literature that an effective amount of HMG-c〇A reductase inhibitory substance is administered in order to increase endothelial cell-nitric oxide synthase activity (application patent scope item 1, paragraph [〇〇1] 〇]). Further, as the hmg-c〇a reductase inhibitor, simvastatin and i〇vastatin can be cited (Patent No. 97, paragraph [0016; | and examples). Further, there are examples in which simvastatin and i〇vastatin are administered for the purpose of measuring ecNOS activity (paragraph [0089]). That is, in the Japanese Patent Laid-Open Publication No. 2003-511347, it is disclosed that the Styda compound has an increase in endothelial nitric oxide synthase activity. In the Japanese Patent Laid-Open Publication No. 2004-149480 (Patent Document 2 below), there is no invention of the invention entitled "Therapeutic agent for ophthalmic diseases for oral or transdermal administration". Specifically, in the fourth application of the document, it is disclosed that there is an improvement in lipid metabolism abnormality selected from meval〇tin, lovastatin, Lipit〇r, Epadel. The medicine is a therapeutic agent for ophthalmic diseases for oral or transdermal administration. Further, in the examples of this document, there is disclosed an example in which the field of view is enlarged by administering Membrane to an open glaucoma patient with high intraocular pressure (paragraph [0008]). Further, the Merrill is a hyperlipidemia therapeutic agent marketed by Sankyo Pharmaceutical Co., Ltd., and its active ingredient is pravastatin which is one of the Stadling compounds. Further, in the seventh application of the document, the target disease includes "eye diseases, glaucoma, retinitis pigments 2 ΧΡ / invention manual (supplement) / 97-01/90138443 7 200824682 degenerative, diabetic retina Lesions, plaque degeneration." In the case of the central retinal venous occlusion, or in the Japanese Patent Laid-Open Publication No. 2004-149480, an example of oral administration of Mie-Bai is disclosed in order to expand the field of view of open glaucoma with high intraocular pressure. However, in this document, a compound considered to be effective for the treatment of retinal color = variability is carnitine (paragraph [〇〇〇9], paragraph [〇〇1〇]), and not a statin compound. Also, in this document, it is considered to be effective in the treatment of diabetic retinopathy, central retinal vein occlusion or macular degeneration, which is a combination of carnitine and taurine (paragraph [〇〇1'3 ]). The most representative complication of retinal detachment is proliferative vitreous retinopathy (PVR: pr0liferative vite〇retin〇pathy), which accounts for 5-10 pPVR of retinal detachment due to benign cell proliferation in the eyeball. In traction retinal detachment caused by PVR, traction occurs directly on the inner and outer surfaces of the retina, eventually leading to detachment of the retina from the retinal pigment epithelium (RpE) layer. A prophylactic treatment for pvR 10 is not yet available. Currently, surgical methods are mainly used to treat PVR. Proliferative vitreoretinopathy (PVR) is characterized by the formation of a constricted cell membrane on both sides of the retina (eg 'Tea photo Fastenberg, et al.,

Am. J. Ohthalmol, Vol. 93, ρρ· 565-572 (1982)). Retinal pigment epithelial (RPE) cells are generally thought to be involved in cell proliferation associated with pVR. If the resting RPE (retinal pigment epithelium) cells move into the vitreous cavity and are in the proper combination of cytokines, the RPE cells divide and differentiate. By this differentiation, cells having the characteristics of myofibroblasts including the 312XP/invention specification (supplement)/97-01/96138443 8 200824682 follow-up and fineness are produced. It is generally believed that if the cell membranes follow the surface of the retina, traction is produced, resulting in retinal detachment. Proliferative vitreoretinopathy (PVR) is caused by the proliferation of intraocular cells (especially R眼c: Replicating Ocular cells) such as retinal pigment epithelial (RPE) cells, and the proliferative membrane contraction and traction of the retina. Therefore, it is generally considered that a medicine or a composition which inhibits proliferation or contraction of such intraocular cells can effectively treat pvR. It is generally believed that such a Lule product or compound can also effectively treat or prevent PVR-related diseases such as diabetic retinal detachment. In the International Publication No. WO97737542 (the following patent documents, there is disclosed a gene therapy method for proliferative vitreoretinopathy (pVR) which is transfected into a replicating oocyte using a retroviral vector. Further, International Publication 1099/00129 A manual method (hereinafter, Patent Document 4) discloses a method for treating a proliferative vitreous retinal 10 membranous lesion (PVR) using a calcium channel blocker. [Patent Document 1] 曰本专利特表2〇()3 [Patent Document 2] Japanese Patent Laid-Open Publication No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. No. Hei. Contents (Problems to be Solved by the Invention) An object of the present invention is to provide a dNA oral inhibitor of retinal vascular endothelial cells, a therapeutic agent for intraocular diseases associated with intraocular diseases, and a 312XP/invention specification (supplement) /97·01/96138443 〇200824682 Prophylactic agent. The object of the present invention is to provide a neovascular inhibitor in the eye; an inhibitor of cell proliferation or a cell contraction inhibitor in the eye; Cell preparation or replication inhibitor of ocular cells; therapeutic or prophylactic agent for exudative senile yellowness; therapeutic or prophylactic agent for atrophic age-related macular degeneration, diabetic retinopathy, traction retinal detachment, vitreous A therapeutic or prophylactic agent for retinopathy of atherosclerotic edema I. A therapeutic or prophylactic agent for uveitis, allergic conjunctivitis or spring conjunctivitis, a therapeutic or prophylactic agent for glaucoma; and prophylactic treatment for proliferative vitreoretinopathy (10) An effective PVR therapeutic or prophylactic agent; and a prophylactic agent for retinal detachment; a therapeutic agent or a pre-treatment agent for retinal vein occlusion. (means for solving the problem) The present invention relates to a therapeutic or prophylactic agent for an intraocular disease, which basically inhibits DNA synthesis of a retinal vascular endothelium based on a fat-soluble Statin compound, prevents cell proliferation, and has An embodiment which inhibits cell contraction, snoring, anti-oxidation and neuroprotection; it contains a statin compound as an active ingredient. Further, the present invention is basically based on the knowledge of the following examples: by using a fat-soluble Statin compound such as simvastatin which is known as an HMG-CoA reductase inhibitor or the like, it is possible to inhibit intraocular cells. Synthetic, thereby effectively inhibiting proliferation and contraction of cells in the eye. Further, the present invention is based on the following observations: inhibition of proliferation or contraction of intraocular cells and prophylactic treatment of proliferative vitreoretinopathy (PVR) 312XP/invention specification (supplement)/97·_6138443 1〇200824682 It can prevent traction retinal detachment. Specifically, the present invention relates to the following invention. [1] A DNA synthesis inhibitor of retinal vascular endothelial cells, which comprises, as an active ingredient, a fat-soluble statin, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof. [2] The synthetic inhibitor of retinal vascular endothelial cells according to the above [1], wherein the above-mentioned fat-soluble Stellarine simvastatin, f luvastatin l〇vastatin or cerivastatin is used in two or more species. [3] The D-synthesis inhibitor of retinal vascular endothelial cells according to the above [1], wherein any one or both of the above-mentioned fat-soluble Statin system simvastatin and fluvastatin. [4] The synthetic inhibitor of retinal vascular endothelial cells according to the above [2] or the above [3], which is administered intraocularly. [5] The D-implication inhibitor of retinal vascular endothelial cells according to the above [2] or the above [3], which has a sustained-release carrier which is administered or disposed in the eye. [6] The inhibitor of retinal vascular endothelial cells according to the above [2] or the above [3], which has a sustained-release drug administered or placed in the vitreous [7] - treatment of an ophthalmic disease An agent comprising, as an active ingredient, a fat-soluble statin, a salt which is permissible by music, or a pharmaceutically acceptable solvate thereof. [8] The therapeutic agent for ophthalmic diseases according to the above [7], wherein the above-mentioned fat-soluble Statin system simvastatin, fluvastatin, 1〇vastatin or 312XP/invention specification (supplement)/97-01/96138443 11 200824682

Any one or two of Cerivastatin may be used as a therapeutic agent for ophthalmic diseases such as the above [7]. Sexuality > Ding is both simvastatin and fiuvastat. Any one of the above-mentioned fat-solubles or [10] is administered intraocularly as in the ophthalmology system of the above [8] or the above [9]. A therapeutic agent for a disease according to the above [8], wherein the therapeutic agent for an ophthalmological disease according to the above [8] has a sustained-release carrier which is administered or disposed in the eye. [12] The therapeutic agent for ophthalmological diseases according to the above [8] or the above [9], which has a sustained-release carrier which is technically or provided in the vitreous. [13] A neovascular inhibitor in the eye which contains a fat-soluble statin, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as an active ingredient. [14] The neovascular inhibitor of the eye as in the above [13], wherein the above-mentioned sputum / glutinous sylvestre / dying simvastatin, f luvas tat in, lovastat in _ or cerivastatin any! Kind or more than two. [15] The neovascular inhibitor in the eye of the above [13], wherein any one or both of the above-mentioned sorghum/glutinal stalks> sifflvastat and f iuvastat in. [16] The neovascularization inhibitor in the eye of the above [14] or the above [15], which is administered intraocularly. [17] The neovascularization inhibitor in the eye of the above [14] or the above [15], which has a sustained-release carrier which is administered or placed in the eye. [18] Neovascularization inhibition in the eye of the above [14] or the above [15] 312XP / invention specification (supplement) / 97 collection / 96138443 12 200824682 "There is a sustained release property of administration or placement in the vitreous Carrier. [19] The neovascular inhibitor in the eye of the above [14] or the above [15] for suppressing the production of new blood vessels from the retina. [20] An intracellular growth inhibitor or cell contraction inhibitor comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient. [21] The cell proliferation inhibitor or cytoskeletal inhibitor in the eye of the above [20], wherein the lipophilic statin is any one or more of simvastatin, _fluvastatin, lovastatin or cerivasta1;in. [22] The cell proliferation inhibitor or cytoskeletal inhibitor in the eye of the above [20], wherein the lipophilic statin is any one or both of simvastatin and fluvastatin. [23] A cell proliferation inhibitor or a cell contraction inhibitor in the eye of the above [21] or the above [22], which is administered intraocularly. [24] A cell proliferation inhibitor or a cell contraction inhibitor in the eye of the above [21] or the above [22], which has a sustained-release carrier which is administered or disposed in the eye. [25] The cell proliferation inhibitor or cell contraction inhibitor in the eye of the above [21] or the above [22], which has a sustained release ‘sex carrier which is administered or placed in the vitreous. [26] An agent for replicating an eye cell proliferation inhibitor or a replicating cell cell contraction inhibitor comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. 312XP/Inventive Manual (Supplement)/97-01/96138443 13 200824682 [2 7] The cell proliferation inhibitor of the replication eye or the cell contraction inhibitor of the replication eye as described above, wherein the above-mentioned fat-soluble Sidajiang system Any one or two of simvastatin, fluvastatin, lovastatin or cerivastatin. [28] The cell proliferation inhibitor of the replication eye of the above [27] or the cell contraction inhibitor of the complex purple eye, wherein any one or both of the above-mentioned fat-soluble Sida juices are simvastatin and fluvastatin. [29] The cell proliferation inhibitor of the replication eye of the above [27] or the above [28], or the cell contraction inhibitor of the replication eye, wherein the intraocular administration is performed [30] as described above [27] or the above [ 28] A cell proliferation inhibitor of the replication eye or a cell contraction inhibitor of the replication eye, which has a sustained release carrier administered or disposed in the eye. [31] The cell proliferation inhibitor of the replication eye of the above [27] or the above [28], or the cell contraction inhibitor of the replication eye, which has a sustained release carrier which is administered or placed in a glass. [32] A therapeutic or prophylactic agent for exudative age-related macular degeneration comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as an active ingredient. [33] The therapeutic or prophylactic agent for exudative senile macular degeneration according to the above [32], wherein the lipophilic statin is one or more of simvastatin, fluvastatin, lovastatin or cerivastatin. [34] The therapeutic agent for exudative age-related macular degeneration according to [32] above or the 312XP/invention specification (supplement)/97·01/96138443 200824682 prophylactic agent, wherein any of the above-mentioned fat-soluble Statin system is simvastatin and fluvastatin One or both. [35] The therapeutic or prophylactic agent for exudative age-related macular degeneration of the above [33] or the above [34], which is administered intraocularly. [36] The therapeutic or prophylactic agent for exudative age-related macular degeneration of the above [33] or the above [34], which has a sustained-release carrier which is administered or placed in the eye. [37] The therapeutic or prophylactic agent for exudative age-related macular degeneration of the above [33] or the above [34], which has a sustained release carrier which is administered or placed in the vitreous. [38] A therapeutic or prophylactic agent for atrophic age-related macular degeneration comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable bath composition thereof as an active ingredient. [39] The therapeutic or prophylactic agent for atrophic age-related macular degeneration according to the above [38], wherein the lipophilic statin is any one or more of simvastatin, fluvastatin, l〇vastatin or cerivastatin. [40] The therapeutic or prophylactic agent for atrophic age-related macular degeneration according to the above [38], wherein the fat-soluble Statin is either or both of simvastatin and fluvastatin. [41] The therapeutic or prophylactic agent for atrophic age-related macular degeneration of the above [39] or the above [4〇], which is administered intraocularly. [42] The therapeutic or prophylactic agent for atrophic age-related macular degeneration of the above [39] or the above [4〇] has a sustained release load administered or placed in the eye

312XP/Inventive Manual (Supplement)/97-01/96138443 H 200824682 [43] The therapeutic or prophylactic agent for atrophic age-related macular degeneration according to the above [39] or the above [40], which has been administered or disposed on A sustained release carrier in the vitreous. [44] A therapeutic or prophylactic agent for diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema or retinopathy of prematurity (especially a therapeutic or prophylactic agent for traction retinal detachment), which comprises a fat-soluble statin, A pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solubilizing agent thereof is used as an active ingredient. U5] The therapeutic agent 2 prophylactic agent (especially the therapeutic agent or prevention of traction retinal detachment) of diabetic retinopathy, traction retinal detachment, bovine edema or retinopathy of prematurity as described above [44]/ , in the above-mentioned fat-soluble Stella; any one or more of the singular simvastatin, fluvastatin, lovastatin or cerivastatiri.春♦ [46] Therapeutic agent 2 preventive agents (especially therapeutic agents or prevention of traction retinal detachment) such as diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema or retinopathy of prematurity as described above [44] Any one or both of the above-mentioned fat-soluble statin simvastatin and fluvastatin. [47] Diabetic retinopathy as described in [45] or [46] above, traction, optometry: membrane peeling, vitreous hemorrhage, macula An edema or retinopathy of prematurity and a cardioprotective or prophylactic agent (especially a therapeutic or prophylactic agent for traction retinal detachment), wherein it is administered intraocularly. 200824682 & or [41] diabetic retinopathy , traction retinal detachment, drusen 廿 廿 final π, godly version of bleeding, macular edema or retinopathy of prematurity 3 treatment d or pre-p prescription (especially the therapeutic agent for traction retinal detachment 5: page defense) Sustained-release carrier administered or placed in the eye. 49] Diabetic retinopathy as described above [45] or [46], traction iron vision = membrane (4), vitreous hemorrhage, macula Edema or premature retinopathy: / oral therapy or prophylactic agent (especially a therapeutic or prophylactic agent for traction retinal detachment), JL, i @士&, ^ ^ Τ It has been administered or placed in the vitreous a sustained release carrier. [50] A therapeutic agent for uveitis, allergic conjunctivitis, or spring conjunctivitis, comprising a fat-soluble historical substance, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof As an active ingredient. [51] The therapeutic agent for uveitis, allergic conjunctivitis or spring conjunctivitis according to the above [5G], wherein the above-mentioned fat-soluble Statin is any one of brewing, fluvastatin, l〇vastatin or ceHvastatin φ or 2 or more. [52] The therapeutic agent for uveitis, allergic conjunctivitis or spring conjunctivitis according to the above [5〇], wherein any one or both of the above-mentioned fat-soluble Statin is simvast Mh and iluvastatin [53] The therapeutic agent for uveitis, allergic conjunctivitis or spring conjunctivitis according to the above [51] or [52] above, wherein it is administered intraocularly. [54] as described above [51] or above [ 52] uveal , a therapeutic agent for allergic conjunctivitis or spring conjunctivitis, which has a sustained release carrier administered or placed in the eye. ' 312XP / Invention Manual (supplement) / 97-01/96138443 17 200824682 _ above & 51] or The therapeutic agent for glucocorticitis, allergic knot or spring conjunctivitis according to the above [52], which has a drug or a sustained release carrier. [56] A therapeutic or prophylactic agent for glaucoma containing fat The soluble Sidajiang, which is pharmaceutically acceptable, is a pharmaceutically acceptable solvent which is an active ingredient. [57] The therapeutic or prophylactic agent for glaucoma according to [56] above, wherein the above-mentioned fat-soluble statin is simvastatin, fluvastatin, lovastatin or cerivastatin, or two or more thereof. [58] The therapeutic or prophylactic agent for glaucoma according to the above [56], wherein the lipophilic statin is one or both of siravastatin and fluvastatin. [59] The therapeutic or prophylactic agent for glaucoma according to the above [57] or the above [58], which is administered intraocularly. [60] The therapeutic or prophylactic agent for glaucoma according to the above [57] or the above [58], which has a sustained release carrier which is administered or placed in the eye. [61] The therapeutic or prophylactic agent for glaucoma of the above [57] or [58], which has a sustained release carrier which is administered or placed in a vitreous. [62] A therapeutic or prophylactic agent for proliferative vitreoretinopathy, which comprises a fat-soluble statin, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as an active ingredient. [63] The therapeutic or prophylactic agent for proliferative vitreoretinopathy according to [62] above, wherein any of the above-mentioned fat-soluble Statin system simvastatill, fluvastatin, lovastatin or cerivastatin is 1 312XP/invention specification (supplement)/97- 01/96138443 18 200824682 species or more than 2 types. [64] The therapeutic or prophylactic agent for proliferative vitreoretinopathy according to [62] above, wherein the above-mentioned fat-soluble Statin, Si is a heart; fluvastatin or both. [65] The therapeutic or prophylactic agent for proliferative vitreoretinopathy according to the above [63] or (10), which is administered intraocularly. [66] The therapeutic or prophylactic agent for proliferative vitreoretinopathy according to the above [63] or [64], which has a sustained-release carrier which is administered or placed in the eye. [67] The therapeutic or prophylactic agent for proliferative vitreoretinopathy according to the above [63] or the above [64], which has a sustained release carrier which is administered or placed in the vitreous. (Effect of the Invention) According to the present invention, a DNA synthesis inhibitor of retinal vascular endothelial cells and a therapeutic agent and a preventive agent for intraocular diseases associated with (d) diseases can be provided. Through the present invention, a neovascular inhibitor in the eye; an inhibitor of cell proliferation or a cell contraction inhibitor in the eye; a cell proliferation inhibitor of the replication eye or a cell contraction inhibitor of the replication eye; exudative age-related macular degeneration Therapeutic or prophylactic agent; therapeutic or prophylactic agent for atrophic age-related macular degeneration, diabetic retinopathy, traction retinal detachment, vitreous-spot edema, therapeutic or prophylactic agent for retinopathy of prematurity; , allergic conjunctivitis or a therapeutic or prophylactic agent for the spring; a lunar ocular agent or prophylactic agent; an effective treatment for proliferative vitreous optic network 312ΧΡ/invention specification (supplement)/97-01/96138443 19 200824682 retinal vein A therapeutic or prophylactic agent for a PVR therapeutic or prophylactic agent for obstructive disease (PVR). [Embodiment] The first aspect of the present invention relates to a DNA synthesis inhibitor of retinal vascular endothelial cells, which comprises a fat-soluble Statin compound, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as an active ingredient . The Statin compound is an active ingredient in the agent of the present invention' and is also referred to as a compound of the present invention. That is, the agent of the present invention contains an effective amount of fat dissolved

Sexuality > A butyl compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. The above-mentioned statin-based compound may, for example, be a compound represented by any one of the following formula (I) (Μ), a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof. . Further, the general formulae (I) to (yj) represent a lactone type, and the general formulae (W) to (]) each represent an acid type corresponding thereto. [Chemical 1]

312ΧΡ/发明发明(补件)/97-01/96138443 20 0) 200824682 In the above formula (1), R11~R can be separated into chlorine atoms, dentate atoms, meridines, and Ci—C6 groups. ΓιΓγ^ιϊ^甘η 土丨匸6 alkoxy, alkyl, c2-C6 alkenyl or C2-C6 alkynyl. Preferably, R' in the formula (1) is c]-C6 alkyl, which is a Ci~c3 alkyl group, and more preferably a methyl group. The ri2 of the second m) is preferably a hydrogen atom, an imine atom, a hydrazine group, or a C1-C3 alkyl group, more preferably a hydrogen atom. The q atom or the meridine group is more preferably a hydrogen atom or a c'-c« 炫 group, and in the formula (1), Rm is a phase H11 atom or a fluorenyl group, respectively. And R15' is preferably Cl-C6 alkyl group c is not "as R14 good A field: a廿 mountain ruler 1 soil is 〇- (: 3 alkyl, especially the methyl group. Among them, better nx The two are methyl groups. At least one of them is preferably a group of R16' of the formula (1), or a c-C3 alkyl group, more preferably a gas atom or a hydroxyl atom. Those who are hydrogen in the general formula (I) X, Rii, methyl and 13 15 hydrogen atoms can be exemplified by Japanese Patent Laid-Open No. 5, R and R16 as Japanese Patent Special Publication No. 59 - 4536 〇? In the general formula (I), ... and R "for the method of the invention, only 15 and R16 are hydrogen atoms, and can be manufactured according to the method disclosed in Japanese Patent No. UR12 and R13, published in the report. In the general formula (1 = Ή (10) and Rl2, R13 and R are 5 hydrogen atoms and Rl6 and Rl4 are methyl are ethyl, according to this patent 312XP / ^ ^ ^ * (ffi #) / 97-01/96138443 21 200824682 Manufactured by the method disclosed in Japanese Patent Publication No. 3-66297. In the general formula (I), 'R, R13 and R14 are fluorenyl groups and rw, Rl5 and Rl6 are hydrogen atoms. Japanese Patent Special Open No. 55_11179 It is produced by the method disclosed in the report. In the general formula (1), 'R", R' Rl, methyl and r12 and r, 6 are hydrogen atoms, which can be disclosed in the Japanese Patent Publication No. Sho 64_1476. The method of the present invention is the production of a compound of the formula (1), wherein R.sup.1, R.sup.1, and R.sup.1, and R.sup.1 is a hydroxy group, and R.sup.6 is a hydrogen atom, which can be produced by the method disclosed in Japanese Patent Publication No. Hei-3-33698. Included in the general formula (1) = each compound, according to the above publication, and a known organic synthesis method [Chemical 2]

In the above-mentioned fascinating (Π) 中一-1 minerals may be the same or different, and the surface is not a ruthenium atom, a dentate atom, a thiol group, a Ci-alkyl group, a Ια cw halogen group, a C2—C6 group, or C2_Ce block base. As the preferred one of the formula (1), it is a hydrogen atom, &

Cl~C6 alkoxylate, more preferably a donor base, especially preferred is 312XP/invention specification (supplement)/97·〇1/96138443 22 200824682. R22 and R23 in the formula (H) may be a hydrogen atom of the benzene ring, and R22 and P, preferably a substituent or a γ-γ ρ is a wind atom, a halogen atom, a hydroxyl group or a d-alkyl group. 'More preferably, hydrogen is a hydrogen atom. f in a gc channel base 'Ultra good general formula (H) R24 and R25 gas B work. ^ π24 is a substituent at any position of the core or helium atom, as R24 and ^, more soil fly nr The earth is a helium atom, a halogen atom, a hydroxyl group or an "alkyl group. More preferably, it is a hydrogen atom-based group. Particularly preferred is a fluorine atom. It is preferred that C3 is preferably ortho or para-position, and more preferably The position of 2 may be any position, compared with a compound in which VR21 is a 1-methylethyl group, and R22 to r24 are hydrogen atoms and is a fluorine atom in the para position, which can be disclosed in Japanese Patent Publication No. Hei 02-46031. _ , to manufacture. The formula U) is included in the formula: according to the above publication and the known organic synthesis method [Chemical 3]

312XP/Invention Manual (Supplement)/97-01/96138443 23 200824682 In the above formula (8), R31 to R37 may be the same or may not be a halogen atom, a halogen atom, a trans group, a pyridyl group, a c, a 'Ci-C6 halogen. Alkyl, C2-C6 alkenyl or C2-c fluorenyl, as β in the formula (dish), preferably 'i =: C oxo' is preferably C, -(d), especially 4 = R32 and f in the formula (ΠΙ) may be a benzene ring as a hydrogen atom, as ..., preferably a gas;::: a group or a group or a CC group 'better' is a hydrogen atom or : Originally a hydrogen atom. In the case of L3, the R34 and R35 in the formula ΟΠ) may be a benzene ring chlorine atom 'as Π R', preferably hydrogen 2: a substituent or a group or an alkyl group, more preferably; The atom and the hydroxyl group are hydrogen atoms. ^Atom or C3 alkyl, especially preferred, the general formula (8) is a benzene ring any argon atom, as R36 and R37, a preferred substituent or a hydrazine C b-M- is a ruthenium atom, a ruthenium atom, a hydroxy ruthenium CrM Base, better is a hydrogen atom

Hyun base, especially good for fluorine atoms. It is better to take the sub or CH bit or the alignment. The position of the soil is Ren Ren', preferably adjacent to the general formula (m), R31 is the armor, 7 f n32 R- is the needle position of the Weng shield methyl ethyl, R to R34 is the hydrogen atom and: A compound of a para atomic gas can be produced by the method disclosed in I7. General formula:: contains: Γ can be produced according to the above publication and known organic synthesis method 312XP / invention specification (supplement) / 97-01/96138443 24 200824682 [Chemical 4]

In the above formula (Ιγ), the difference ' denotes a hydrogen atom, a dentate atom, and its ': Guangtong can also be C6-burning oxygen, r'^-based, Cl-C6 alkyl, c!-R43 * 1 6 Haloalkyl, C2-C6 alkenyl, or c2-c6 alkyne R represents an atom and a dentin atom U alkynyl

Oxygen, C 〖-. 6 calcining group, C2—c: a group represented by a Cl—C6 alkyl group, a c6-sinter-R46-R47 group, a R46# _ decenyl group, a C2_C6 alkynyl group or a fluorenyl group represented by the formula R47, a force er, a dibu Ce Stretching base or G2 - an alkenyl group, 4 Ll - C6 alkoxy group. R41 in the formula (IV) is more preferably a halogen atom, a C-C6 alkyl group or a group than the C6 alkoxy group. 〃, C3 alkyl, especially preferably Ι-f-based B as the formula (jy) in the 42 C--C6 alkoxy group, more preferably the base 0 is preferably a hydrogen atom, C!~ Cs alkyl or alkyl, especially preferably methyl ethyl as the reverse 4 in the general formula (IV), preferably argon atom C! a c6 alkyl, 312XP / invention specification (supplement) / 97-01/96138443 200824682

The Cl—c6 alkoxy group or the group represented by the formula n-Ca alkoxy group or Cl—C3 ’ ’ is more preferably “Ci”. R in the general formula (IV) "and R45 may be a terpene atom, as "and R45, a more substituent or a c--r which is a halogen atom, a halogen atom, a hydroxy group, and more preferably an alkane. The base, especially the position of the dentate atom or the Cl - c3 position m substituent is arbitrary, preferably ortho or para, more preferably para. k horse is in the formula (IV), 42 US, R44 is gas, - methyl ethyl, R43 is a compound of methoxy-methyl as a para-position atom, and can be based on the composition of the above-mentioned publications and well-known organic [Chemical 5]

In the above formula (V), R51 to R53 may be the same or different, and represent hydrogen atom, halogen atom, hydroxyl group, Ci-C6 alkyl group, Ci-alkoxy group, 312XP/invention specification (supplement) )/97-01/96138443, < 200824682

Cl-C6 haloalkyl, c2~c6η Γ _Γ ru alkenyl, or c^c6 alkynyl, γ represents hydroxy, c f61 oxalate alkoxy, Cl-C6 haloalkyl, c2-c6 alkenyl, C2 - c6 alkynyl, ...S〇2H, -s〇2n(ch3)2^ r1 56S〇2NH2 ^ ^s〇2NH(CH3) ^ may be the same or different bases of HR households, R1R56 oxy, C... burnt base, ==Cl; C6 burn one-difficult, _S〇 secret, C2-C6 alkynyl, ^2NH(CH3), or -S02N(CH3)2. . R51' in C=AV) is preferably a hydrogen atom, a Cl-Ce alkyl group or a Li-u-alkyl fluorenyl group, more preferably a human base group. It is a Cl—C3 alkyl group, and particularly preferably 1-methylethyl hydrazine, which may be a substituent at any position of the benzene ring or 3c—: R53, preferably a hydrogen atom, a dentate atom, and a The alkyl group is more preferably a hydrogen atom or a halogenated group, and particularly preferably a gas atom. Take the C1-C3 bit or the alignment, preferably the alignment. The position is Rensi', preferably R51 in the adjacent _H it formula (V), preferably a non-base. Preferably, 1^ and π are a radical, a c 1 kg or a 3' more preferably a C1 - a S 2 CH4. Li Wanma S〇2H or in the general formula (V), I^ is two, and the two-part one-pass two (four) 2648897 published in the publication 312XP / invention manual (supplement) 辄 27 27 200824682 [Chemical 6]

In the above formula (VI), R61~r65 a & may be the same or different, and the table c does not: 'Γ原二素素, 经基, Cl~C6(四), Cl-Ce, oxy, Make A? 6 alkenyl,. 6 alkynyl or C3-Cl° cycloalkyl. As R61 in the formula (VI), preferably r to r ^ ^ ^ 乜 is a ruthenium atom, a G-C6 alkyl group, a decyl decane emulsifiable group or a fluorene-cycloalkane is preferably a cyclopropyl group. ^ is a burnt group, 862 and R63 in the general formula (VI) can be! 笱 calendar; from & n62 R is a substituent or a ruthenium atom in the position of J-cloth, as 1^ and R63, more beautiful痞Γ — Γ I- basin is a ruthenium atom, a halogen atom, a hydroxy-Ci Ce alkyl group, and more preferably a hydrazine 屌r ^ ^ is a hydrogen atom. ^Atom or G-channel, especially good R64 and r65 in formula (VI) π 1 J ^ This is the source of the inferior atom at any position, as R "and r65 bauxite into 弋Γ ^ ^ 1 is a wind atom, a halogen atom, Hydroxyl or C丨-C6 alkyl, more preferably to the helmet 7 Ding Yingong r, η soil. It is a wind atom, an i atom or a C!-c3 alkyl group, and particularly preferably a fluorine atom. Instead of doing 10, it is arbitrary from the position of '^, preferably Zheng or opposite, and better is the opposite.狂狂局 郇 312XP / invention manual (supplement) /97-01/96138443 28 200824682 In the general formula (VI), R61 is a cyclopropyl group, R62 to R64 are hydrogen atoms, and R65 is a para-fluoride atom. It can be manufactured by the method disclosed in Japanese Patent No. 2569746. Each compound contained in the formula (VI) can be produced by the above-mentioned publication and a known organic synthesis method. [Chemistry 7]

m In the above formula (W), R11 to R16 have the same meanings as in the above formula (I). [化8]

312XP/Invention Manual (Supplement)/97-01/96138443 29 200824682 In the above formula (Μ), R21 to R25 have the same meanings as in the above formula (Π). [Chemistry 9]

In the above formula (IX), R31 to R37 have the same meanings as in the above formula (dish). [化10]

312XP/Invention Manual (Supplement)/97-01/96138443 30 200824682 In the above formula (X), R41 to R45 have the same meanings as in the above formula (IV). [化11] HQ, ^γ~οο〇Η

In the above formula (XI), R51 to R54 have the same meanings as in the above formula (V). [化 12]

_ In the above formula (M), R61 to R65 have the same meanings as in the above formula (VI) phase 312XP/invention specification (supplement)/97-01/96138443 31 200824682. As a compound of the present invention, preferably, the statin compound is derived from r lovastatin, simvastatin, cerivastatin, atrovastatin, rosuvastatin, fluvastatin, pi tavastatin, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof. Any one or two or more compounds selected from the group consisting of. Among these, it is preferably a group consisting of "lovastatin, s imvastat in, cer i vastat in, f luvastat in, its pharmaceutically acceptable salt, and its pharmaceutically acceptable solvate" Any one or two or more compounds selected from the group. Furthermore, it is more preferably one or two or more compounds selected from the group consisting of "simvastatin, fluvastatin, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof". Further, the Statin compound is usually fat-soluble. On the other hand, among the Statin compounds, pravastatin is a highly hydrophilic agent. 0 Stella lamps other than pravastatin are usually fat soluble. The present invention relates to a pharmaceutical agent containing a statin-based compound other than pravastat i η, that is, a fat-soluble statin-based compound as an active ingredient. In the present specification, the term "Cx - Cy" means that the base to which it is attached has X to y carbon atoms. As the "halogen atom", fluorine, chlorine, bromine or moth can be mentioned. - "G-C6 alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include an anthracenyl group, an ethyl group, a n-propyl group, an isopropyl group, and an n-butyl group. , isobutyl, t-butyl, tert-butyl, n-pentyl, isopentyl, 312XP/invention specification (supplement)/97-01/96138443 32 200824682 1,1-dimethyl^one T-sign ΓΛ / sign, and is the base. The "G-C6 alkoxy group" is a linear or branched alkoxy group having a carbon number of 丨~6, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. Base, butyloxy, chloro-bupropoxy, tert-butoxy 1-pentyloxy. The "c, -C6-dentate alkyl group" is an alkyl group in which the above-mentioned "Ci_Ce alkyl group" is substituted by one or a plurality of halogen atoms, and examples thereof include a monofluoromethyl group and a difluoro group: : 3 mouse 3' base two. , 2'Γtrifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 3,3' 3-di-propyl, perfluoropropyl, 4-fluorobutyl, cardiac chloride Midea, 4-bromobutyl, and perfluorohexyl. The earth, "C2-C6 alkenyl" is at any position of the above "alkyl group" and the number of linear or branched carbon atoms of two or more double bonds is 2 to 6, and the column may be, for example, ethylene. Base, propylene, 2-propenyl, isopropyl: :; hexyl, U-butadienyl, 2-pentenyl, 3-pentenyl, and /hexyl. • “C2 — C6 block base” means a straight or branched chain block having a three-bonded carbon atom and having 2 to 6 carbon atoms at any position of the above-mentioned “alkyl group”. Block group, 1-propynyl group, and 2-propyl group. "G-C6 alkylene group" means a linear or branched alkyl group having a carbon number of 1-6. For example, Methylene, ethyl, 3, diethyl, ethyl, U-dimethylethyl, U-dimethyl: ex situ, 2,2-dimethylexyl, 1,2, 2-tri Methyl extended ethyl, 1'\2'2-tetramethylethyl, and propyl. Soil, "C2-C6-extended alkenyl" means that the number of carbon atoms in a linear or branched chain is 2 312XP / invention specification (supplement) / 97-01/96138443 „ 200824682 ~ 6 of the county, can be cited : 伸乙县, 乙methyl stretch vinyl, 2_methyl stretch vinyl, I dimethyl stretch vinyl, 1,2-didecyl vinyl, propylene, propyl propyl, 2-methyl propyl a dilute group, a 3-methacryl group, a butenyl group, and a pentenyl group. The "C3-Ch cycloalkyl group" is a cycloalkyl group having 3 to 1 ring carbon atoms, and examples thereof include a ring. Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl. The term "salt" as used in the pharmaceutically acceptable salt, means "salt" which means a fat-soluble salt of a butyl compound. In addition, in the present specification, "the pharmacy is combined with the smuggling of the smugglers. The statin compound can form a salt according to a usual method. As the salt, for example, sodium salt, potassium salt or lithium salt can be mentioned. An alkali metal salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; a metal salt such as an aluminum salt, an iron salt, a salt, a copper salt, a nickel salt or a cobalt salt; an inorganic salt such as an ammonium salt; a third octylamine salt; ¥基amine salt, morphine salt, glucosamine salt, phenylglycine sulphonate, succinylamine salt, N-methyl glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, Dicyclohexylamine salt, N,N,-dibenzylethylenediamine salt, procal procaine salt, procaine salt, diethanolamine salt, " phenylethylamine salt" An amine salt such as an organic salt such as a tetramethylammonium salt or a tris(sulfonyl) aminyl methane; a hydrohalide of hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid; a mineral acid salt such as a chlorate, a sulfate or a phosphate; or a salt of a lower alkane sulfonic acid such as sulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; a stupid stone; base Acid salt; a salt of an amino acid such as glutamic acid or aspartic acid, a salt of a carboxylic acid such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid; Organic acid; and ornithine 312XP/invention specification (supplement)/97-01/96138443 34 200824682 Amino acid salt such as salt, face amine salt, aspartic acid salt, etc. Preferably, the "sodium solvate" means a solvate of a fat-soluble Stella lamp-based compound. As for the solvate, a hydrate is mentioned. Further, the statin compound is placed on the solvate. Absorbing moisture in the atmosphere or by recrystallization and sucking

Attached with water to form a hydrate. The case of forming such a solvate is also included in the solvate thereof, and the various compounds are contained in the compound of D. For example, the Sterling Dings compound has optical isomers. A stereoisomer of R coordination and s coordination exists in the compound of the present invention. The compound of the present invention also includes each stereoisomer or a compound containing an isomer thereof in an arbitrary ratio. Such a ruthenium isomer can be obtained by synthesizing a statin-based compound using an optically active raw material compound or, if necessary, optically isolating the statin-based compound by a usual optical resolution method or separation method. Further, the Statin type compound has geometric isomers such as a cis form and a trans form. The compounds of the present invention also comprise geometric isomers or compounds containing such geometric isomers in any ratio. Hereinafter, salts, solvates, and isomers, also referred to as compounds of the present invention, are also included. The first aspect of the present invention also provides a method for inhibiting Dna synthesis of a retinal gold tube endothelial cell comprising the step of administering a compound of the present invention to a subject. As demonstrated by Example 1 (Fig. 1) and Example 2 (Fig. 2), which will be described later, only the 'Minute glutinous rice stalk> butyl sulfonate compound inhibits DNA synthesis of vitreous cells and retinal vascular endothelial cells. As for the object, humans or mammals other than humans can be cited. Further, the method of administering the compound of the present invention to a subject 312ΧΡ/invention specification (supplement)/97-01/96138443 35 200824682 is as described later, but preferably the administration method is injection under the Ten〇n capsule or the vitreous body. Or implant a sustained release agent (sustained release carrier) or the like and directly inject it into the eye. A first aspect of the invention also provides the use of a compound of the invention for the manufacture of a DNA synthesis inhibitor of retinal vascular endothelial cells. The first aspect of the present invention relates to an intraocular neovascularization inhibitor comprising the compound of the present invention as an active ingredient. As the compound of the present invention, the above-mentioned compound of the present invention can be suitably used. As demonstrated by Example 2 (Fig. 2) described later, the fat-soluble Statin system compound inhibits DNA synthesis of retinal blood vessel-endothelial cells. Further, as demonstrated by Example 3 (Fig. 3) described later, the fat-soluble Statin compound inhibits proliferation of retinal endothelial cells. Further, as evidenced by Example 4 (Figs. 4(A) and (B)) described later, the fat-soluble glutamate > butyl compound inhibits Tube format ion in the venous endothelial cells of the meridian. The retinal vasculature of the eye is blood stasis, so it is generally considered that the 10Tube format ion is also inhibited in the retinal vascular endothelial cells. Thereby, the fat-soluble statin compound inhibits the proliferation of retinal vascular endothelial cells, and at the same time effectively suppresses the state of pathological neovascularization and the pathological growth of neovascularization. Therefore, the compound of the present invention is effective for preventing or treating age-related macular degeneration (especially atrophic age-related macular degeneration or exudative age-related macular degeneration). 'HMG-CoA reductase inhibitors are known to inhibit the proliferation of human vascular endothelial cells by inhibiting the geranylgeranylation of RhoA (J〇urnal af the American Society of Nephrology, june 2004, 312XP/Inventive Manual ()) /97-01/96138443 36 200824682 ν〇1· 15,2429—2439). The fat-soluble Statin compound is JJMG —

The CoA reductase inhibitor is therefore considered to have a vascular endothelial cell proliferation inhibitory function and has a function as an intraocular neovascularization inhibitor. Further, according to Example 13 (Figs. 14(A) and (B)) and Example 14 (Figs. 15(A) and (B)), it was revealed that a lipophilic statin compound inhibits VEGF-induced KDR (VEGF receptor 2). Phosphorylation and lithic acidification of p44/42 MAP kinase. According to these examples, it is explained that the fat-soluble statin-based compound exhibits a proliferation inhibitory effect on endothelial cells by inhibiting not only the Rh 〇 signal transmission pathway but also the MAp kinase signal transmission pathway. The second aspect of the present invention also provides an intraocular neovascularization inhibiting method comprising the step of administering a compound of the present invention to a subject. As for the object, humans or mammals other than humans can be cited. Further, the method of administering the compound of the present invention to a subject is as described later, and the preferred method of administration is to inject into a Tenon capsule or a vitreous body, or to provide a sustained-release carrier or the like and directly to the eye. The first aspect of the present invention also provides a use of a compound of the invention for the manufacture of an intraocular #neurovascular inhibitor. Further, as the compound of the present invention, one of the compounds (including pharmaceutically acceptable salts thereof or pharmaceutically acceptable solvates thereof) contained in the compound of the present invention may be used, or two of them may be used. The above is used in combination as appropriate. A third aspect of the present invention relates to a diabetic retinopathy, a traction retinal detachment, a glare, a macular edema, a retinopathy of prematurity, an angiogenic glaucoma or an optic nerve disorder comprising the compound of the present invention as an active ingredient. A therapeutic or prophylactic agent. Among these, there are, inter alia, therapeutic or prophylactic agents for traction retinal detachment. As the compound of the present invention 312XP / invention specification (supplement) / 97 also / 96138443 200824682, the above-mentioned compound of the present invention can be suitably used. As described by Example 2 (Fig. 2) described later, the fat-soluble Statin compound inhibits DNA synthesis of retinal vascular endothelial cells. Further, as demonstrated by Example 3 (Fig. 3) described later, the fat-soluble Statin compound inhibits the proliferation of retinal vascular endothelial cells. Further, as demonstrated by Example 4 (Figs. 4(A) and (B)) described later, the compound of the present invention inhibits the formation of new blood vessels in umbilical vein endothelial cells. Therefore, it is considered that the compound of the present invention also inhibits the formation of new blood vessels in the retinal vascular endothelial cells which form venous blood vessels. According to these Examples 2 to 4, etc., the fat-soluble Statin system compound not only inhibits the proliferation of retinal vascular endothelial cells, but also effectively suppresses the occurrence of pathological neovascularization and the development of pathological neovascularization. When the hyperglycemia state continues, the retina is fine: the tube is blocked, and the retina is in an anoxic state, which results in a new blood vessel. This pathological new blood vessel wall is brittle and easily broken, so it is easy to cause vitreous hemorrhage. In addition, if bleeding occurs, it will cause cell proliferation, which can form a film that covers the skin, thus causing traction retinal detachment. With regard to the addition of diabetes, there are also pathological new blood f, and glassy

Si: the possibility of two traction retinal detachment. Further, if a pathological state occurs, and the officer is pressed, the pressure rises to produce angiogenic glaucoma. In the right: the blood of the right 4 is produced in the pericytes of the optic nerve cells and causes the optic nerve disorder. Therefore, the compound of the present invention can effectively prevent or treat diabetic retinopathy of dry eye, vascular new 312 ΧΡ / invention instructions (supplement) / 97-01/96138443 38 200824682 glaucoma or optic nerve disorder. After that, there will be new blood in the eye. η Membrane surgery, etc. Ophthalmology surgery, silly sputum, new blood, there are diseases caused by neovascularization, namely angiogenic glaucoma, vitreous hemorrhage, traction retinal detachment or The possibility of optic nerve disorders. Because of the fat-soluble history; the Dinghua character effectively inhibits the development of pathological neovascularization, the compound of the present invention can effectively prevent the disease q caused by neonatal blood f after surgery, and can be used as the compound of the present invention. One of the above-mentioned compounds (including a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof) contained in the compound of the present invention, or a combination of two or more thereof may be appropriately combined. A third aspect of the invention provides a method for the treatment of diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, angiogenic glaucoma or optic nerve disorder comprising the step of administering a compound of the invention to a subject Method or preventive method. As for the object, humans or mammals other than humans can be cited. Further, the method of administering the compound of the present invention to a subject is preferably described below, and it is preferably administered by injection into a Tenon capsule or into a vitreous body, or a sustained release carrier or the like is directly administered to the eye. A third aspect of the invention also provides a compound of the invention for use in the manufacture of a therapeutic or prophylactic agent for diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, angiogenic glaucoma or optic nerve disorder The way. A fourth aspect of the invention relates to a therapeutic agent for uveitis, allergic conjunctivitis, or spring conjunctivitis comprising the compound of the invention as an active ingredient. As the compound of the present invention, the above-mentioned 312XP/invention specification (supplement)/97-01/96138443 39 200824682 compound of the present invention can be suitably used. HMG-CoA reductase inhibitors inhibit pentadieneization of proteins and inhibit Rho GTPase located downstream, and the results also inhibit the I_CAM pathway (promoting the path of lymphocyte migration) (The J〇urnai μ

Immunology ' 2005, 174, PP. 2327-2335). Further, inhibition of Rh0 GTPase inhibits the production of cytokines such as IL_8, McP-, and 叩10 located downstream thereof. Further, as evidenced by Example 12 (see Fig. 13) described later, the fat-soluble Stadin-based compound reduced the intranuclear migration amount of the transcription factor NF_"subunit B, i.e., p65. NF — /cB is a transcription factor involved in the production of inflammatory cytokines. Therefore, it is generally considered that fat-soluble statin compounds inhibit the production of inflammatory cytokines by reducing the intranuclear migration of NF-/cB. In other words, it is considered that the inflammatory cytokine can be inhibited by the fat-soluble Statin compound, and therefore the compound of the present invention can inhibit inflammation caused by uveitis, allergic conjunctivitis, or spring conjunctivitis, and thus can be effectively used as Treatment of uveitis, allergic conjunctivitis, or spring conjunctivitis. Further, the compound of the present invention can inhibit inflammation caused by proliferative retinal vitreopathy, diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, angiogenic glaucoma or optic nerve disorder. The compound of the present invention can also be effectively used as a cause of diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema, retinopathy of prematurity, angiogenic glaucoma or optic nerve disorder. A therapeutic agent for inflammation. Further, it is generally considered that the compound of the present invention can effectively prevent or treat intraocular inflammation which can be produced after ophthalmic surgery. Further, as a compound of the present invention, 312XP/invention specification (supplement)/97-01/96138443 Δη 200824682 may be used for all the compounds contained in the above-mentioned compound of the present invention (including the salt thereof, One of them or a pharmaceutically acceptable solvate thereof, or a combination of two or more thereof. A fourth aspect of the invention also provides a method of treating uveitis allergic conjunctivitis or spring conjunctivitis comprising the step of administering a compound of the invention to a subject. As for the object, human or mammals other than humans can be cited. Further, the method of administering the compound of the present invention to a subject is as follows. Preferably, the method of administration is carried out under the TenTn capsule or in the vitreous body or by providing a sustained-release carrier and directly administering it to the eye. A fourth aspect of the invention also provides the use of a compound of the invention for the manufacture of a therapeutic agent for uveitis, allergic conjunctivitis, or spring conjunctivitis. The fifth aspect of the present invention relates to a therapeutic or prophylactic agent comprising the compound of the present invention as an effective moon-eye. As the compound of the present invention, the above-mentioned compound of the present invention can be suitably used. It can be seen from Example 1 (see Figs. 10 (A) and (B)) and Example ι (see Figure h) which will be described later, _ 曰 曰 / 谷 斯塔 达, / 糸 糸 compound inhibits myosin (jjjy 〇S In ) Phosphorylation of the light chain. The inhibition of cell bone architecture was inhibited by inhibiting phosphorylation of the myosin light chain. As a result, cell contraction was inhibited (Circ Res 2002, 91, ρρ·143-150). Therefore, it is considered that the intraocular cell contraction is inhibited by the fat-soluble Statin compound, thereby preventing the increase of intraocular pressure; and by inhibiting the contraction of vascular cells, the blood vessel can be relaxed and the intraocular pressure can be lowered, thereby preventing glaucoma. This can improve the symptoms of glaucoma. Further, as the compound of the present invention, all of the compounds (including pharmaceutically acceptable salts thereof or pharmaceutically acceptable salts thereof 312 ΧΡ/invention specification (supplement)/97-01 which are contained in the above-mentioned compounds of the present invention can be used. One of the compositions of the composition of the composition of the present invention, or a combination of two or more of them. According to a fifth aspect of the present invention, there is provided a method of treating or preventing glaucoma comprising the step of administering a compound of the present invention to a subject. As for the object, humans or mammals other than humans can be cited. Further, the method of administering the compound of the present invention to a subject is preferably as described later, and it is preferred to administer the method/mainly to the underside of the Tenon capsule or the vitreous body or to provide a sustained-release carrier or the like, and to deliver it to the eye. A fifth aspect of the invention also provides the use of a compound of the invention for the manufacture of a therapeutic or prophylactic agent for glaucoma. A sixth aspect of the invention relates to a therapeutic or prophylactic agent for proliferative vitreoretinopathy (pVR) containing the compound of the present invention as an active ingredient, a therapeutic agent for proliferating diabetic retinopathy, a prophylactic agent for traction retinal detachment, and retinal vein occlusion Proliferation or contraction inhibitors of intraocular cells. The "proliferative vitreoretinopathy therapeutic agent," means, for example, "medicine _ product" for the prophylactic treatment of proliferative vitreoretinopathy in a patient at risk of proliferative vitreoretinopathy. Further, the "proliferative diabetic retinopathy therapeutic agent" means, for example, "medical reduction product for prophylactic treatment of proliferative diabetic retinopathy of a patient suffering from proliferative diabetic retinopathy". As demonstrated by Example 16 (refer to Fig. 17) described later, in the rabbit pVR model, the fat-soluble Statin system significantly inhibited the progression of PVR. Fig. 17 is a graph for evaluating the effect of simvastatin on the PVR of the rabbit PVR model based on the progress classification of the PVR shown in Fig. 18. Figure 18 is a diagram showing the progress classification of the PVR. The progress classification in Figure 18 is as follows. 312XP/Invention Manual (supplement)/97-01/96138443 42 200824682 Stage Characteristics "o Z Normal Eye" 1 Intravital Membrane 2 Local traction, localized management changes, congestion, blood, expansion, i tube bulge 3 Localized exfoliation 4 Retinal extensive dissection, complete exfoliation of the pulpy tissue, retinal detachment around the nipple® 5 Complete retinal detachment, retinal folds and retinal tears, as described in Example 1 below (see figure and implementation) As shown in Example 11 (see Fig. 11), the fat-soluble Statin compound inhibits phosphorylation of the kinesin light chain. By inhibiting the phosphorylation of the myosin light chain, inhibition of changes in the cytoskeleton structure results in inhibition of cell contraction. (Circ Res 2002, 91, ρρ· 143 - 150) Further, in Examples 5 to 8 and 19 (Figs. 5 to 8 and 19) which will be described later, the history of fat solubility is also shown. The contraction of vitreous cells. Therefore, the compound of the present invention can be effectively used as a therapeutic or prophylactic agent for proliferative vitreoretinopathy, a therapeutic agent for proliferative diabetic retinopathy, and traction. Membrane exfoliation preventive agent, therapeutic agent or prophylactic agent for retinal vein occlusion, and proliferative/contraction inhibitor of intraocular cells. The prophylactic agent for traction retinal detachment of the present invention comprises an effective amount of the compound of the present invention as an active ingredient. Prophylactic agent for retinal detachment, a prophylactic agent for retinal detachment, specifically, a prophylactic agent for traction retinal detachment containing the compound of the present invention as an active ingredient. As a 312XP/invention specification (supplement)/97-01/ 96138443 43 200824682 The compound of the present invention in the prophylactic agent for inducing retinal detachment is preferably a fat-soluble statin > butyl compound. The so-called "prophylactic agent for traction retinal detachment" is used to prevent the occurrence of traction retinal detachment. In the case of "tractive retinal detachment", the "retinal retinal detachment" of proliferative vitreoretinopathy may be exemplified by retinal detachment caused by proliferative vitreoretinopathy or proliferation of intraocular cells, or by Retinal detachment caused by contraction of the proliferating membrane. That is, as retinal detachment of the present invention, : The proliferative tissue formed in the vitreous body shrinks due to diabetic retinopathy or retinal vein occlusion, thereby causing retinal detachment of the retinal detachment by retinal detachment. As shown in Examples 1 and 2 (Figs. 1 and 2) described later When a fat-soluble Statin compound is used, DMA synthesis of intraocular cells can be inhibited. Further, as shown in Examples 3 to 9 (Figs. 3 to 9), proliferation of intraocular cells (especially replicating eye cells) can be prevented. Or a contraction state. Further, as shown in Example 13 (Figs. 14(A) and (B)), the fat-soluble Stella lamp compound inhibits phosphorylation of 〇R (VEGF receptor); further, as in Example #14 (Fig. 15 (A) and (B)), the fat-soluble Statin system compound inhibits phosphorylation of MAP kinase p44/42 and prevents proliferation of cells in the eye. Further, as shown in Example 15 (Figs. 16(A) and (B)), the fat-soluble Statin system compound significantly inhibited traction retinal detachment in the rabbit PVR model. Therefore, the agent containing the compound of the present invention can be effectively used as a prophylactic agent for traction retinal detachment. As a compound of the present invention, a fat-soluble Statin compound is preferable because the intracellular migration property of the fat-soluble statin is excellent and it is easy to act on cells. As described in Examples 5 to 8 and 19 (Fig. 5 to Fig. 8 312 ΧΡ / invention specification (supplement) / 97-01/96138443 44 200824682 and Fig. 19), as a fat-soluble statin compound, sunvastatin and f luvastatin The vitreous cell contraction inhibition effect is remarkable. On the other hand, pravastatin, which is a water-soluble Statin compound, does not necessarily exhibit a vitreous cell contraction inhibitory action. Therefore, as the compound of the present invention, a lipophilic Sida (4) compound is preferred. The therapeutic or prophylactic agent for retinal vein occlusion of the present invention is a therapeutic or prophylactic agent for retinal vein occlusion which contains the compound of the present invention as an active ingredient. Retinal vein occlusion is caused by high gold pressure or compression of veins. The liposoluble Stadin-based compound inhibits phosphorylation of the myosin light chain as evidenced by Example 1 (Fig. 1 (a) and (B)) described later. By inhibiting the phosphorylation of the myosin light chain and inhibiting cell contraction, it is possible to suppress vasoconstriction and suppress an increase in blood pressure. Further, according to Examples 1 to 3 (Figs. 1 to 3), the fat-soluble Statin compound inhibits DM synthesis and sub-suppresses proliferation of cells. Further, according to Examples 13 and 15 (Figs. 14 and 15), the glutathione > glutathrin-based compound inhibits phosphorylation of the somatic KDR involved in cell proliferation or phosphorylation of map kinase p44/42. It is generally believed that through these embodiments, it is possible to prevent a situation in which the vein is compressed due to cell proliferation of the periphery or blood vessels. Therefore, the compound of the present invention can be effectively used as a therapeutic or preventive agent for retinal vein occlusion. The proliferation/contraction inhibitor of the intraocular cells of the present invention is an agent for inhibiting proliferation or contraction of intraocular cells in an effective amount of the compound of the present invention. 4° Specifically, the proliferation and contraction inhibition of the intraocular cells of the present invention The agent is an intraocular cell containing the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof as permitted in the pharmaceutically acceptable solvate of 312XP/invention specification (supplement)/97-01/96138443 45 200824682 Proliferation and contraction inhibitors. As the compound of the present invention in the proliferation/contraction inhibitor of intraocular cells, simvastatin is preferred. The present invention may also have other uses 'basically, prophylactically treating proliferative vitreoretinopathy (pvR) by inhibiting proliferation or contraction of cells in the eye, and prophylactically ✓ oral proliferative diabetic retinopathy And prevent traction retinal detachment. Therefore, examples of the cells in the eye include retinal pigment epithelial (RPE) cells, glial cells, fibroblasts, fibroblasts, macrophages, and hyalin cells (hyai〇Cyte). As shown in Examples 5 to 8 and 19 (Figs. 5 to 8 and 19) to be described later, one of the candidates for the vitreous cell system is used as an intraocular cell. According to the examples described later (Fig. n, the compound of the present invention inhibits DNA synthesis of vitreous cells. DNA synthesis by cell proliferation] inhibits proliferation of vitreous cells by inhibiting DNA synthesis. Further, according to Examples 5 to 8 described later And 19 (Fig. 5 to Fig. 8 and Fig. 19), the compound of the present invention inhibits contraction of a contractile cell membrane. Therefore, as for the proliferation/contraction inhibitor of the intraocular cells of the present invention, inhibition of proliferation of vitreous cells is exemplified. Or a therapeutic agent for proliferative vitreoretinopathy, a therapeutic agent for proliferative diabetic retinopathy, a prophylactic agent for traction retinal detachment, and a proliferation/contraction inhibitor of the intraocular cells (medicine of the present invention), The compound of the present invention containing an effective sputum. Here, the effective amount means the treatment for proliferative vitreoretinopathy, the proliferative diabetic retinopathy double/oral treatment, the prevention of traction retinal detachment or the intraocular cells. Proliferation and suppression are effective amounts. That is, the proliferative vitreoretinal 312XP/invention specification of the present invention (Supplement) / 97-〇厅138443 46 200824682 Agent, prophylactic agent for retinal detachment, and proliferation of intraocular cells · Good-formulation 'provided with the compound of the present invention as an active ingredient - including an effective amount The present invention provides a method for treating proliferative vitreoretinopathy as a component of an active ingredient, and a prosthetic fork to a subject (human or non-human mammal). Further, the present invention provides an effective amount of the active ingredient. A method for treating a proliferative diabetic condition in which a compound of the invention is administered to a retina (/τΜ or a non-human mammal). Further, the present invention provides a method comprising administering an effective amount of the compound of the present invention to an object. (4) Prophylactic methods for preventing retinal detachment (steps of human or non-human 4 feeding animals). The invention also provides an effective amount of the compound as an active ingredient to a subject (human or non-human breastfeeding) The step of the animal) = the method for inhibiting the proliferation of the inner cells and the method for inhibiting the contraction. These preferred complaints are as described above. Use of the compound of the present invention for producing a therapeutic agent for proliferative vitreoretinopathy. The present invention provides a compound for use in the manufacture of a therapeutic agent for diabetic diabetic retinopathy, which is provided by K. Use of a compound of the present invention for producing a pre-protective agent for traction retinal detachment. Further, the present invention provides a use of the compound of the present invention for producing a proliferation/contraction inhibitor of intraocular cells. In the case of the above-mentioned prophylactic or therapeutic agent (hereinafter also referred to as "the agent of the present invention"), the compound can be administered to itself. M2XP/Invention Manual (Supplement)/97-01/96138443 47 200824682 Alternatively, a pharmaceutically acceptable carrier or the like may be mixed and administered. Moreover, it can be combined with the composition of the sex #二::: knives and then can be administered with the sustained release: body, and "post-in the vitreous. The specific compound of the present invention can be used as a target disease. The administration, the setting target, the administration route, and the like are used as the field. The administration amount of the compound of the present invention is, for example, when the injection is administered to the Tenon capsule or the injection is administered to the vitreous body, generally:言 'For adults (body weight 6 〇 kg), each eye is administered 1 χ 1 〇 2 tons 'preferably 1 Χ 10, ~ 5 x l 〇 2 Μ, more preferably 丨 μ ~ 5 χ 1 〇 2 : ΓΛ, for example, the invention can be The compound is mixed with a diluent or the like: a preparation of the present invention. In the present invention prepared as described above, the above-described syringe is used to administer the agent of the present invention to the eye of the patient: the number of persons can be appropriately adjusted, for example, Once a day, the agent containing the compound of the present invention, the donor, etc. can also be administered in the near future of the operation. When the above agent is administered to a human or a mammal other than a human, if appropriate The dosage can be converted into the amount of 60 kg body weight. The route may be exemplified by intraocular administration by intramuscular administration of a fat-soluble Stella (four) compound to specifically treat or prevent intraocular diseases. The present invention also provides a sustained release device (sustained release device). a method of treating various diseases in which a step of immersing a fat-soluble stagnation compound in a vitreous body of a globule or a vitreous body is delivered to the vitreous of the eyeball. # The agent of the present invention may be a medicament containing a sustained-release carrier ( Specifically, it is a sustained-release drug containing an active ingredient in the carrier. Further, in the present invention, it is preferable to administer or release the sustained-release body to the eye, and it may be a buried vein. The gap between the membranes, the subretinal, the intrascleral, or the vitreous. Further, the present invention also provides a fm / treatment for the treatment of the body of the 312XP / invention specification (supplement) / 97-01/96138443 200824682 Sustained release of disease: the knowledge: the use of biologic cut-off compounds. The so-called "body" means a device that can release the drug in a controlled state for a long time. The compound of the present invention can be used as its own, or as: As a compound containing the present invention As was: Example 3 has a tolerance of ::: the music acceptable carrier, diluent or excipient person.

For example, when the drug (4) of this (4) is used as an eyedrop or as an injection (4), if an effective amount of the compound of the present invention and a known diluent (the diluent is contained in a carrier acceptable to music), Injection can be. As the diluent, there may be mentioned water such as "bacterial water, pure water, distilled water, physiological food _,: glucose solution; alcohol such as ethanol; polyhydric alcohol such as glycerin, propylene glycol, polyethylene-2; sterilized organic solvent; Water-based temple powder; any of the pBS (squamous acid buffer) or a mixture of two or more thereof. The present invention: a pharmaceutical agent can be easily produced by mixing a compound of the present invention as an active ingredient with a diluent or the like. Further, the manufactured drug of the present invention can be appropriately enclosed in an ampoule and stored. μ eye drops or injections containing the compound of the present invention may suitably contain a blood-removing component such as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, neostigmine methyisulfate, and tropinamide ( Helmets such as tropicamide; zinc sulfate, zinc lactate, allantoin, ε-aminocaproic acid, indomethacin, chlorinated lysozyme, etc.; acitazan〇last, amlexanox , ibudi last, "trani last, diphenhydramine hydrochloride and other antihistamines or 312XP/invention specification (supplement)/97-01/96138443 49 200824682 anti-allergic ingredients, amino acids; A local anesthetic such as XybUpr〇Caine, cocaine hydrochloride, corne caine, and dibucaine hydrochloride. It may also contain: chondroitin sulfate, hyaluronic acid-specific tackifier; surfactant such as chloroaniline; preservatives such as sodium benzoate, ethanol, hydroxychloroaniline; fungicide or antibacterial agent; hydrochloric acid, boric acid a pH adjuster such as sodium hydroxide or sodium hydrogencarbonate; an isotonic agent such as sodium hydrogen sulfite, sodium sulfite or potassium chloride; menthol, camphor, mint oil, peppermint oil (peppermint 〇u) Such as a fragrance or a cooling agent; a buffer such as a citric acid buffer or the like. Further, it may further comprise a mucosal mimetic polymer, a gelled polysaccharide, a finely divided carrier matrix or a combination of these components as a sustained sustained release component. The sustained release carrier containing the compound of the invented means a device which releases the drug in a controlled state for a long period of time. Examples of the sustained-release carrier useful in the present invention can be found, for example, in U.S. Patent No. 5,378,475, U.S. Patent No. 5,773, and U.S. Patent No. 5,902,598. These documents are incorporated herein by reference. As for the sustained-release carrier, those having a structure that is "purely placed in the eye" can be cited. Specifically, a person who has a spiral body portion to be embedded in the eye and a drug storage portion in the spiral body portion can be cited. In the case of a sustained-release carrier of such a shape, the compound of the present invention can be slowly released by containing the compound of the present invention and rotating the helical body to fix it: heart, eyeball. X, since the main body portion is spiral, the surface area of the sustained-release carrier becomes large, and the compound of the present invention can be released in the eye. Thereby, the agent of the present invention can be effectively administered continuously. A pharmaceutical agent of the present invention may be a tablet, a capsule, a granule, a powder, a syrup 312XP/invention specification (supplement)/97-01/96138443 5〇 200824682 2, etc. In this case, as the pharmacological limb, it can be exemplified by excipients, diluted swords, 1 jin=load stabilizer, and continuation odorant, suitable agent, phlegm, and Sida (4) organisms. A variety of pharmacological effects, :::,: due to fat-soluble preparations, and directly to the eye. J土 JE Non-oral injection The agent of the present invention can be produced by a known method. Eye drop or note

The compound of the present invention is added to a diluent or the like, and is further prepared. The tablet can be subjected to a keying agent by, for example, mixing a pharmaceutical composition obtained by mixing a 14-unit (four) body with a tableting machine, for example, by encapsulating the compound of the present invention into a capsule or the like. Manufactured in a carrier. & The pharmacological effects of the compound of the present invention can be measured by the pharmacological test method described in the examples below or by the method thereof. In the following examples, the following abbreviations have the following meanings. Undefined abbreviations have a generally accepted meaning. _ °c=degree Celsius hr = hour mi η = minute sec = second // Μ = micromolar concentration mM = millimolar concentration M = molar concentration / / L = microliter mL = ml 312XP / invention manual (supplement )/97-01/96138443 51 200824682 β g=micro-immunity mg=mg DMEM=Dulbecco's Modified Eagle's Medium FBS = fetal bovine serum trypsin — EDTA = trypsin_ethylenediaminetetraacetic acid PBS = phosphate buffered physiological saline TNF — = tumor necrosis factor PDGF - BB = platelet-derived growth factor HGF = hepatocyte growth factor TGF - /3 = transforming growth factor PVR = proliferative vitreoretinopathy simvastatin used in this example, available from LKT Laboratories, Inc. (2233 University Ave West St. Paul MN 55114, USA) purchased. The test disclosed below was repeated three times unless otherwise specified, and the data obtained by a representative experiment (average soil SD) was also revealed. In the normally distributed group, when using the student t test and p < 0.05, it was considered statistically significant. [Example 1] Inhibition of simvastatin on DNA synthesis of hyalocytes stimulated by TNF-a, PDGF-BB, HGF In order to investigate simvastatin (SS) on vitreous cells stimulated by TNF-a, PDGF-BB, HGF The effect of DNA synthesis ability was performed while [3Ή] thymidine incorporation assay. 312ΧΡ/Invention Manual (Supplement)/97-01/96138443 52 200824682 Bovine vitreous cells were maintained in DMEM medium (Sigma, Japan) supplemented with 1% fetal calf serum (FBS). The vitreous cells were cultured on a Petri dish coated with type 1 collagen (Iwaki, japan) at 37 C in 5% c〇2, 95% air, and the medium was changed every 2 to 3 days to maintain . 4 to 5 subcultured cells were used for the experiment. The vitreous cells were seeded on 24 porous plates in 1 〇 4 cells/well in DMEM containing 1% FBS, and the serum concentration was lowered to 3% after 24 hours, and allowed to stand for 24 hours. Thereafter, treatment was carried out for 30 minutes in the presence or absence of simvastatin at 0·1 //Μ, 〇·3 //Μ, 1·〇, and then 5 ng/mL of TNF-α, 10 ng/mL PDGF-ΒΒ, 20 ng/mL of HGF was treated for 18 hours. The cells were then exposed to [mercapto-3H] thymidine (Amersham) for 6 hours to reach 20 / z Ci / mL. After washing the cells with PBS, trichloroacetic acid was fixed and recovered, and the amount of [mercapto-3H] thymidine incorporation was measured by a sputum counter. In the long section > in the chart, 'from left to right respectively, simvastaUn 〇# μ, 〇·1 //Μ, 0·3 //Μ, 1·〇φ by TNF — α, PDGF — ΒΒ, HGF The bovine vitreous cells were treated, and the sputum synthesis was increased to about 1.12 times, 1.36 times, and 1.28 times, respectively, compared with the untreated control group. Simvastatin inhibits DNA synthesis by all stimulated cells of these cells. Figure 1 shows the effect of simvas1:atin on DNA synthesis of glass-selling cells. As shown in Fig. 1, the increase in DNA synthesis induced by tnf-j, PDGF-BB, and HGF was significantly inhibited by simvastatin. [Example 2] simvastatin Retinal 312 stimulated by VEGF, HGF, TNF-α/invention specification (supplement)/97-01/96138443 53 200824682 Inhibition of DNA synthesis of vascular endothelial cells (REC) In order to investigate simvastatin (SS For the effect of sputum synthesis of retinal vascular endothelial cells stimulated by VEGF, HGF, and TNF-α, [3Η] thymidine incorporation assay was performed. The study was carried out in the same manner as in Example 1 using retinal vascular endothelial cells isolated and cultured from bovine eyeballs. The cytokine concentrations used were: VEGF (25 ng/mL), HGF (25 ng/mL), and TNF-α (10 ng/mL). Simvastat in is administered in such a way as to achieve 0 /z Μ, 0· 1 # Μ, 0·3 // Μ, 1.0 //Μ. As shown in Fig. 2, the increase in DNA synthesis induced by VEGF, HGF, and TNF-α was significantly inhibited by 1 // simvastatin. [Example 3] Inhibition of cell proliferation by simvastatin acid To investigate the inhibitory effect of simvastatin acid on the proliferation of VEGF-induced bovine retinal vascular endothelial cells, a cell number assay was performed. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Next, on each plate, simvastatin acid (SSS) was administered at a final concentration of 0.1 μΜ, 1·0 μΜ, 10 //M, respectively. After 24 hours, stimulation was performed with VEGF (25 ng/mL) and allowed to stand for 48 hours. As shown in the graph of Figure 3, it was revealed that simvastatin inhibited the proliferation of bovine retinal vascular endothelial cells due to VEGF stimulation in a concentration-dependent manner. 312XP/Invention Manual (Supplement)/97-01/96138443 54 200824682 [Example 4] _ simvastatin inhibition of tube format ion in VEGF-induced retinal vascular endothelial cells To investigate the inhibitory effect of simvastatin on vascular expression in VEGF-induced retinal vascular endothelial cells, tube formation assay (jk tube) Form analysis). Kurabo's angiogenesis kit (KZ-100) was used and the experiment was performed according to the attached operating instructions to evaluate the lumen formation ability. First, * A 24-well plate co-cultured with human umbilical vein endothelial cells (HUVEC) and fibroblasts was cultured in an attached medium (KZ-1 500) to simvastatin (l from M), Pravastatin (l // Μ) was treated for 30 minutes and then stimulated with VEGF (25 ng/mL). The culture solution was replaced with a new culture solution on days 4, 7, and 9. The cells were fixed on the 11th day of stimulation, HUVEC was stained with anti-CD-31 antibody, and the area of the formed lumen was measured using the attached angiogenesis software (KSW-5000U), and statistical analysis was performed. As shown in the photograph of Fig. 4(A) and the graph of Fig. 4(B), 1 //M simvastatin significantly inhibited vascular endothelial cell-derived vascular endothelial cell formation. From this result, it was revealed that simvastatin inhibits neovascularization due to VEGF stimulation. [Example 5] Inhibition of contraction of collagen gel containing vitreous cells stimulated by proliferation factors by T simvastatin In order to investigate the effects of simvastatin and pravastatin on the proliferation of 312XP/invention specification (supplement)/97-01/96138443 55 200824682 The inhibitory effect of the contraction of the collagen gel of the vitreous cells stimulated, and the collagen gel shrinkage analysis was performed. Bovine vitreous cells were maintained in DMEM medium supplemented with 10% fetal bovine serum (FBS). The vitreous cells were cultured in DMEM medium supplemented with 10% FBS in DMEM medium supplemented with 10% FBS at 37 ° C at 37 ° C in a cultured soy (Iwaki, Japan) coated with type 1 collagen. The medium was changed every 2 to 3 days to maintain it. Cells of 3 to 6 continuation were used for the experiment. The vitreous cells were treated with trypsin-EDTA for 3 minutes, washed with *MEM, and then collected again in DMEM. The type 1 collagen protein, the reconstituted buffer, the suspended vitreous cells, and distilled water were mixed on ice at a ratio of 7:1:1:1. The mixture was placed on a 24-well plate (Nunc, Roskilde, Denmark) and incubated at 37 ° C for 60 minutes in 5% C 〇 2, 95% air. After performing the above gelation operation, 0.5 mL of DMEM supplemented with 3% FBS was injected into each well of a 24-well plate. After 24 hours of gelation, the gel was separated from the wall surface of the plate using a micro spatula for experiments. For the collagen gel prepared in the above manner, TGF-/3 2 , simvastatin, and pravastatin were administered, respectively. The diameter of the collagen gel was measured by the ruler on the 5th day after the stimulation. TGF-β 2 (3 ng/mL), and simvastatin or pravastatin were respectively administered to a collagen gel containing vitreous cells to achieve 0 /z Μ, 0·1 /z Μ, 0. 3 // Μ, 1· 0 // Μ. According to Figure 5, simvastatin intentionally inhibits collagen gel shrinkage due to TGF-2-2 at concentrations above 0.3 /ζ. 312ΧΡ/Invention Manual (Supplement)/97-01/96138443 56 200824682 [Example 6] Inhibition of contraction of collagen gel containing vitreous cells stimulated by proliferation factor by simvastatin acid and fluvastatin In order to investigate simvastatin, pravastatin, fluvastatin Collagen gel shrinkage analysis was performed on the inhibitory effect of contraction of a collagen gel containing viable cells stimulated by a proliferation factor. In the same manner as in Example 5, each concentration of simvastatin S complex (live simvastatin), pravastatin, _f luvastatin was treated for 30 minutes, and stimulated with TGF — 々 2 (3 ng/mL) for 5 days. The diameter of the gel was measured and the shrinkage was evaluated. From Figures 6(A) and (C), simvastatin and fluvastatin inhibit collagen gel shrinkage due to TGF-cold 2 at concentrations above 1 // Μ. [Example 7] Inhibition of contraction of collagen gel containing φ vitreous cells stimulated with proliferation factor by simvastatin and fluvastatin In the same manner as in Example 5, simvastatin (SS) was administered in a manner of 10 // 分别, respectively. ), f luvastatin (FS) and pravastatin (PS), evaluated the inhibitory effect on collagen gel shrinkage due to TGF-n2 stimulation. Fig. 7 shows the inhibitory effect of simvastatin and fluvastatin as a fat-soluble statin compound on gelatin gel shrinkage due to TGF /5 2 . [Example 8] 312XP/Invention Manual (Supplement)/97-01/96138443 57 200824682 Inert simvastatin, active simvastat; in (simvastatin acid) Contraction of collagen gel containing vitreous cells stimulated by proliferation factors Inhibition In order to investigate the inhibitory effect of the inert type simvastat iη and the active type simvastatiη on the contraction of the collagen gel containing the proliferation factor-stimulated vitreous cells, collagen gel shrinkage analysis was performed. In the same manner as in Example 5, the inhibitory effect of simvastatin and simvastatin acid (active simvastatin) on contraction of collagen gel due to TGF - / 3 2 sputum was evaluated. In Fig. 8(B), the active simvastatin is at a concentration above 1 // ,, and in Figure 8 (A), the inert simvastatin is inhibited by TGF-Lu 2 at a concentration above 3 // 分别Contraction of collagen gel. [Example 9] Inhibition of simvastatin on contraction of collagen gel containing T10-M1 cells of T cell-/3 2-stimulated Muller cells in order to investigate simvastatin for 含有0 containing TGF-β 2 stimulation - Collagen gel shrinkage analysis was carried out by inhibiting the contraction of the collagen gel of Μ1 cells. The collagen gel contraction study was carried out in the same manner as in Example 5 using ΜΙ0-M1 as a cell strain of Muller cells. TGF was administered to a collagen gel containing MIO-M1 cells - cold 2, and simvastatin and pravastatin were administered separately to achieve 0 // Μ, 0·1 #Μ, 0·3 #Μ, 1·0 /zM. From Fig. 9(A), simvastatin 312XP/invention specification (supplement)/97-01/96138443 58 200824682 inhibits collagen gel shrinkage due to TGF-/3 2 at concentrations above 0.1 /ζ. [Example 10] Inhibition of myosin light chain phosphorylation in TGF-Silver-stimulated vitreous cells by simvastatin, f luvastatin, pravastatin Western blotting to study simvastatin, f luvastat in, pr a vast at in Effect of acidification of myosin light chain in vitreous cells stimulated by TGF - / 3 2 . ® Study of phosphorylation of myosin light chain (MLC) by Western blotting. The vitreous cells in starvation were treated with simvastatin (SS), fluvastatin (FS), and pravastatin (PS) (10 // 分别, respectively) for 30 minutes, and stimulated with TGF - / 3 2 for 24 hours. After washing the cells with Phosphate Buffered Saline (PBS), add lxLaemmli buffer (50 mM Tris-HCl [pH 6.8], 2% SDS, 10% C) with protease inhibitor and phosphatase inhibitor. Triol) extracts whole cel 1 lysate. The extracted total cell lysate was electrophoresed and transferred to a nitrocellulose membrane by the 808-? person 0 £ method. Blocking with 3% skim milk, an anti-phosphopho-MLC antibody was added as a primary antibody, and the reaction was allowed to stand overnight at 4 °C. After washing the nitrocellulose membrane, a horseradish peroxidase (HRP)-conjugated anti-IgG antibody was added as a secondary antibody (diluted 4000-fold) to react with the primary antibody. Luminescence was carried out using an ECL detection system manufactured by Amersham. In order to correct the amount of protein, an anti-MLC2 antibody was used as a primary antibody, and an anti-IgG antibody that binds HRP was used as a secondary antibody, and 312XP/invention specification (supplement)/97·〇1/9613 8443 59 200824682 was used for detection of MLC2. . Use NIH image to analyze the luminescence process. The above experiment was performed 3 times, and the difference in performance was statistically analyzed. The pMLC/MLC of the control group was set to 1 〇〇% in the graph. ° According to Figure 10, simvastatin, fluvastatin intentionally inhibits myosin light chain phosphorylation in TGF - /3 2 stimulated vitreous cells. The results revealed that simvastatin and iluvastatin inhibited cytoskeletal changes due to acidification of myosin light chain. [Example 11] _ Inhibition of myosin light chain phosphorylation by TGF-Silver 2-stimulated vitreous cells caused by simvastatin acid (SSS), mevalonic acid or fragrant The inhibitory effect of pyrophyllin-based pyrophosphoric acid was studied by Western blotting method: the inhibitory effect of Simvastatin on the light chain linonication of myosin in TGp /5 2-stimulated vitreous cells depends on the dihydroxyl Inhibition of conversion of HMG-c〇A to di- valeric acid in the valeric acid pathway, or inhibition of geranylgeranylation. The vitreous cells were added to 3/Μ sim simvastatin acid (SSS), and dihydroxy valeric acid (; MeV) or geranylgeranyl pyrophosphate was treated at each concentration for 24 hours, respectively. TGF - cold 2 for 24 hours of stimulation. Western blotting method was used in the same manner as in Example 1 to study the acidification of MLC. Figure 11 is a photograph of the results of the Western blot method, which is a substitute for the dihydrovaleric acid or geranylgeranyl-based acid for simvastatin acid 312XP/invention specification (supplement)/97-01/96138443 60 200824682 Schematic diagram of the inhibitory effect of jin on the inhibition of TGF12-stimulated facial light chain scurification. Such as the stomach „ protein know S1D1VaStatin on the GF-Wan 2 stimulated vitreous body =, inhibition of protein light chain phosphorylation, by m's muscle coagulation or 5 (10) leaf base geranyl pyrophosphate into two St can explain that ' si _stat i η inhibits di-methyl group: y. w: t inhibits geranyl geranyl group. Figure 12 shows the outline of di-m-methylvalerate path [Example 12] ^ si The effect of simvastatin on the nuclear migration in vitreous cells was studied by western blotting method using Western blotting method. The vitreous cells were treated with simvastatin (1 VM) before each time. -a (lQ ng/mL) for 4 hours of stimulation. Using φ CelLytic NuCLEAR extraction Kit (SIGMA), according to the operation

The nuclear protein is extracted from the recovered cells. Using the extracted nuclear protein, the performance of p65 (NF - "Subunit of B") was studied by Western blotting in the same manner as in Example 7. Further, in order to correct the amount of protein, it was detected again with an anti-gapdh* antibody. Figure 13 is a photograph of the results of the Western blot method, which is a substitute for the effect of _ simvastatin on the amount of p65 nuclear migration in vitreous cells. In Figure 13, from left to right, the control group (TNF-α and simvastatin untreated), TNF-α treatment for 4 hours, and 312ΧΡ/invention specification (supplement)/97-01/96138443 61 200824682 palpitations (10)11 treatment G, Bu 4, 1G, 24 hours results. Fig. 13 shows that the amount of nuclear migration of 'P65 in the vitreous cells treated by Simvastatin for 24 hours is reduced, so that siinvastatin can inhibit inflammatory cytokines which are regulated by NF-zcB. [Example 13] simvastatin acid (SSS) inhibits keratinization of VDR induced by vegf in bovine retinal endothelial cells by immunoprecipitation and Western blotting studies of simvastatin on VEGF induced by VEGF in bovine retinal endothelial cells The inhibition effect.

Bovine retinal endothelial cells were cultured for 24 hours in a culture medium supplemented with bovine serum. After 24 hours, simvastatin acid was administered in such a manner as to reach 〇 # M, j # M, 丨〇 # M, and the control group or 25 ng/ml of VEGF was added for 5 minutes. Thereafter, the extract of the recovered cells was subjected to immunoprecipitation with an anti-flk-1 antibody, and pKDR or KDR was detected by Western blotting using an anti-phosphorylated flk-1 antibody or an anti-fl-1 antibody. Furthermore, KDR binds to f 1 k-1 to form a receptor for VEGF on the cell membrane. Therefore, an anti-flk-1 antibody was used as an antibody for immunoprecipitating KDR, and in the Western blot method, an anti-phospho-NK_1 antibody or an anti-Π k-1 antibody was used for detection of pKDR or KDR. Figure 14 is a graph showing the inhibitory effect of simvastatin acid (SSS) on phosphorylation of KDR induced by VEGF in retinal endothelial cells. Fig. 14(A) is a photograph of the Western blot method, which is a graph in which the upper half represents the amount of KDR phosphorylated and the lower half represents the total KDR amount. Figure 14 (B) shows the pKDR/KDR value of the cells when the simvastatin acid is 0 // Μ and will be fused with 25 ng/mL VEGF 312XP / invention instructions (supplement) / 97-01/96138443 62 200824682 A graph of the ratio of pKDR/KDR values for each stimulated cell at 100%. From Figure 14, simvastatin acid concentration-dependently inhibits the acidification of KDR induced by VEGF. This shows that simvastatin acid inhibits the acidification of KDR induced by VEGF. [Example 14] Inhibition of phosphorylation of p44/42 MAP kinase induced by VEGF by simvastatin acid (SSS) In the same manner as in Example 13, the simvastatin acid was evaluated by VEGF-induced p44/ in the same manner as in Example 13. The inhibitory effect of 42 MAP kinase on can acidification. The concentration and treatment time of simvastatin acid and VEGF were also the same as in Example 13. In order to study the effect of simvastatin acid on cell proliferation, a phosphorylation assay of P44/42 MAP kinase was performed as an indicator of proliferation response. Simvastatin acid inhibited the phosphorylation of p44/42 MAP kinase induced by VEGF in a concentration-dependent manner. φ Figure 15 is a graph showing the inhibitory effect of simvastatin acid (SSS) on phosphorylation of p44/42 MAP kinase (MAPK) induced by VEGF. Fig. 15(A) is a photograph of the Western blot method, which is a graph in which the upper half indicates the amount of phosphorylated p44/42 MAPK and the lower half indicates the total p44/42 MAPK amount. - Figure 15(B) shows that the value of [ρρ44/42 MAPK]/[ρ44/42 MAPK] of the cells stimulated with VEGF of 25. ng/mL is set to 100% when simvastatin acid is 0 // Μ A graph showing the ratio of [ρρ44/42 MAPK amount]/[p44/42 MAPK amount] values of each stimulated cell. From Figure 15, it is revealed that simvastatin acid inhibits phosphorylation of VEGF-induced p44/42 MAP kinase 312XP/invention specification (supplement)/97-01/96138443 63 200824682. [Example 15] Inhibition of traction retinal detachment of rabbit pvr model by simvastatin The rabbit pvR model induced by fibroblasts was used to study the inhibition of simvastatin on traction retinal detachment. For rabbits undergoing vitreous surgery, one of the group of simvastatin and simvastatin was administered to the vitreous cells of the fibroblasts. The simvastatin was administered to the group, and the same concentration of simvastatin was administered 1 day after, 3 days, 5 days, and 7 days after vitrectomy. The indirect ophthalmoscope was used after the 28th day after surgery. Figure 16 (A) was not administered to simvasta1. :in photo of the rabbit pVR model eye. A proliferative membrane was observed in the vitreous cavity, and the proliferating membrane pulled the retina and caused traction retinal detachment. The photograph was taken from a photograph of the eye of a rabbit PVR model of s imv as tat in at a concentration of 15 μ μ. A small increase in colonization was observed, but traction retinal detachment was inhibited. As shown in Figure 1β, simvastatin inhibits traction retinal detachment in a rabbit PVR model induced by fibroblasts. [Example 16] - Inhibition of PVR by rabbit simvastatin (SS) - The rabbit PVR model induced by fibroblasts was used to study the inhibition of PVR by simvastatin. The experiment was conducted in the same manner as in Example 15. Fig. 17 is a graph showing the inhibitory effect of simvastatin on the PVR of the rabbit PVR model based on the progress classification of the PVR shown in Fig. 18 to evaluate the effect of 312XP/invention specification (supplement)/97-01/96138443 64 200824682 simvastatin. That is, in the present embodiment, the progress of the PVR is evaluated based on the classification of the PVR progress as illustrated in Fig. 18. As a result, in the rabbit administered with simvastatin of 15 //M, the progress of PVR was suppressed. As shown in Figure 17, simvastatin inhibits the progression of PVR in a rabbit PVR model induced by fibroblasts. [Example 17] Inhibition of contraction of collagen gel containing vitreous cells stimulated by a proliferation factor by simvastatin (SS), lovastatin (LS), and cerivastatin (CS) ® In order to investigate the effects of simvastatin, lovastatin, and cerivastatin on the proliferation factor TGF - /52 stimulated the contractile inhibition effect of the collagen gel of the vitreous cells, and the collagen gel shrinkage analysis was performed. In the same manner as in Example 5, the inhibitory effects of simvastatin, lovastatin, cerivastatin and pravastatin on contraction of collagen gel due to TGF Xin /5 2 stimulation were evaluated. They were treated with 5 μΜ of the statin compound for 24 hours, and stimulated with 3 ng/mL of TGF-10,000 for 5 days. Figure 19 is a graphical representation of the inhibition of simvastat in (SS), fluvastatin (FS), lovastatin (LS), and cerivastatin (CS) on contraction of collagen gels containing TGF - /3 2 stimulated vitreous cells. Fig. 19 (A) is a photograph of a pattern of a collagen gel in the case of administration of simvastatin, lovastatin, f luvastatin (FS), and pravastatin (PS). Fig. 19(B) is a photograph of a pattern of collagen gel in the case of 312XP/invention specification (supplement)/97-01/96138443 65 200824682 cerivastatin (CS) instead of lovastatin. Fig. 19 shows the inhibitory effect of simvastatin, fluvastatin, lovastatin, and cerivastatin on collagen gel shrinkage due to TGF-20,000 as a fat-soluble Stella; (Industrial Applicability) The agent of the present invention can be utilized, inter alia, in the pharmaceutical industry for the manufacture of ophthalmic medicines. [Simplified illustration of the drawings] Fig. 1 shows that simvastatin is used in the vitreous cells. Necrosis factor-a, tumor necrosis factor-a), PDGF-BB (platelet-derived growth factor-BB, j& l small plate-derived growth factor-BB), HGF (hepatocyte growth factor) A chart of the effects of DNA synthesis. Figure 2 is a graph showing the effect of simvastatin on DM synthesis induced by VEGF (vascular endothelial growth factor), HGF or TNF in endothelial cells of the retina jk. Figure 3 is a graph showing the effect of simvastatin acid on the proliferation of reticular vascular endothelial cells induced by VEGF. Fig. 4(A) is a photograph in place of a diagram showing the result of tube formation (iL tube forming ability). The three photographs in the upper half of Fig. 4(A) indicate that no VEGF was added, and the three photographs in the lower half of Fig. 4(A) indicate that VEGF was added. Fig. 4(B) is a graph showing the lumen area of each well when the area of the lumen 312XP/invention specification (supplement)/97-01/96138443 66 200824682 is set to 1% in the case where VEGF is not added. In the long bar graph of Fig. 4(B), the left side 3 indicates that no VEGF is added, and the right three indicates that VEGF is added. Figure 5 is a graph for verifying the contraction inhibition effect of simvastatin. Fig. 5(A) shows a photograph of a pattern replacing the collagen gel, and Fig. 5(B) shows that the collagen gel of each well is set when the collagen gel diameter is set to 100% when simvastatin is not added. A chart of the diameter of the glue. Figures 5(c) and _(D) show the results of using pravastatin instead of simvastatin. The photographs and graphs in Fig. 5 show simvastat in (or pravastatin) 0 // Μ (control group), 0·1 // Μ, 0·3 // Μ, 1 from μ from left to right. Figure 6 is a graph for verifying the contraction inhibition effect of simvastatin. Fig. 6(A) shows a photograph of a pattern of a collagen gel in place of the case of administering a sodium salt of simvastatin. Fig. 6(B) shows a photograph of a pattern of a collagen gel instead of the case of administering pravastatin. Fig. 6 (C) shows a photograph of a collagen gel in place of the case of administration of fiuvastatin. Figure 7 is a graph showing the inhibitory effect of simvastatin and fluvastatin on the contraction of collagen gel containing vitreous cells stimulated by TGF-/3 2 (transforming growth factor-/3 2). Figure. Fig. 7(A) shows a photograph of a collagen gel in place of simvastatin (SS), fluvastatin (FS), and pravastatin (PS). Fig. 7(B) shows the case where the diameter of the collagen gel 312XP/invention specification (supplement)/97-01/96138443 67 200824682 to which the TGF-cold 2 and the statin compound are not added is set to 100%, A graph of the diameter of the collagen gel in the well. Fig. 8 is a graph for demonstrating the inhibitory effect of inert simvastatin and active simvastatin on contraction of collagen proteins containing vitreous cells stimulated by proliferation factors. Fig. 8(A) is a photograph showing a pattern of a collagen gel in the case of administering an inert type of simvastatin, and Fig. 8(B) is a view showing a collagen gel in the case of administering an inert type of simvastatin. Photo. ® Figure 9 is a graph showing the inhibition of simvastatin on contraction caused by a collagen gel containing a cell line of TGF-2 stimulating Muller cells (i.e., ΜΙ0-M1 cells). Fig. 9(A) shows a photograph of a collagen gel instead of the case of administration of siravastatin. Fig. 9(B) shows a photograph of a pattern of a collagen gel in place of the case of administration of pravastatin. Fig. 10(A) is a photograph of the results of the Western blotting method, which is a substitute for the inhibitory effect of simvastatin on the phosphorylation of the TGF/5/2-dependent myosin light chain in vitreous cells. The upper half of the photograph represents the amount of acidified myosin light chain (MLC) and the lower half represents the total myosin light chain. Fig. 10(B) is a graph showing the ratio of the pMLC/MLC value of each stimulated cell when the pMLC/MLC value of the cells to which the TGF-Call 2 and the Statin compound are not added is 100%. In the figure, SS represents simvastatin, FS represents fluvas tat in, PS represents pravastatin, and C represents a control group. 312XP/Inventive Manual (supplement)/97-〇1/96138443 68 200824682 Figure 11 is a photograph of the results of the Western blotting method, which is replaced by a pair of TGFs that are made by simvastatin simvastatin acid. Stimulation of the inhibition of vicination of the myosin light-spinning of the vitreous cells, the inhibition of the effect of diterpene valeric acid or geranylgeranyl pyrophosphate. Fig. 12 is a schematic diagram showing the path of the dihydroxy valeric acid. Figure 13 is a photograph of the results of the Western blot method, which is a substitute for the effect of verifying the effect of simvastatin on the nuclear migration of p65 in vitreous cells. Figure 14 is a graph showing the inhibitory effect of simvastatin acid (SSS) on phosphorylation of KDR induced by VEGF in retinal endothelial cells. Fig. ι4 (Α) is a photograph of the Western blot method. The figure indicates that the upper half represents the KDR amount of phosphorylation and the lower half represents the total KDR amount. Figure ι4 (Β) indicates

A graph of the ratio of pKDR/KDR values for each stimulated cell when the pKDR/KDR value e of the cells stimulated with 25 ng/mL of VEGF was set to 0 and simvastatin acid was set to 0. Fig. 15 is a graph showing the effect of simvastatin acid (SSS) on the inhibition of dishing of p44/42 MAP kinase (MAPK) induced by VEGF. Fig. 15(A) is a photograph of the Western blot method, which is a graph in which the upper half indicates the amount of phosphorylated p44/42 MAPK and the lower half indicates the total p44/42 MAPK amount. Fig. 15(B) shows the case where the value of [ρρ44/42 MAPK]7 [p44/42 MAPK amount] of the cells stimulated with VEGF of 25 ng/mL is set to 100% when the simvastatin acid is 〇μΜ. A graph of the ratio of [PP44/42 MAPK amount]/[p44/42 MAPK amount] values of each stimulated cell. 312XP/Invention Manual (Supplement)/97-01/90138443 69 200824682 Fig. 16 is a photograph in place of a graph showing the inhibitory effect of simvastatin on traction retinal detachment in a rabbit PVR model. Figure 16 (A) is a photograph of the eye of a rabbit PVR model not administered simvastatin. Figure 16 (b) is a photograph of the eye of the rabbit PVR model administered simvastatin. Fig. 17 is a graph for evaluating the inhibitory effect of simvastatin on the PVR of the rabbit PVR model based on the PVR progress classification as shown in Fig. 18. Figure 18 is a diagram showing the progress classification of the PVR. Figure 19 is used to verify the contraction of simvastatin (SS), lovastatin (LS), 061^¥ & 3^31^11 (〇8) for collagen gels containing vitreous cells stimulated by 16卩/3 2 A diagram of the suppression effect. Fig. 19(A) shows a photograph of a pattern of a collagen gel in the case of administration of simvastatin (SS), lovastatin (LS), f luvastati n (FS), and pravastatin (PS). Fig. 19(B) is a photograph showing the pattern of the collagen gel in the case where lovastatin (LS) was administered instead of cerivastatin (CS). Fig. 19(C) is a graph showing inhibition of contraction of collagen gel containing vitreous cells stimulated with TGF - /32 by simvastatin (SS), lovastatin (LS), and cerivastatin (CS). 312XP/Invention Manual (supplement)/97-01/96138443 70

Claims (1)

200824682 X. Patent application scope: 1 2: = Synthetic inhibitor of retinal vascular endothelial cells, which contains a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable bath composition thereof as an active ingredient. Human 1:::? Patent range No. 1 of the retinal vascular endothelial cell leg mouth P 1 'where the above fat-soluble Studa (four) simvastatin, ί luvastatin, 1〇vm ten p ten in ten soil species or more than two . Or (9) (10) gamma, any of the above-mentioned fat-soluble history lines and fluvastatm, or both of the above-mentioned fat-soluble history lines. (2) The DNA synthesis inhibitor of retinal vascular endothelial cells of the second or third aspect of the patent, wherein the intraocular administration is carried out. 5. The DNA synthesis inhibitor of retinal vascular endothelial cells according to claim 2 or 3, which has a sustained release carrier which is administered or disposed in the eye. 6. The MA synthesis inhibitor of retinal vascular endothelial cells as claimed in claim 2 or 3, which has a sustained release carrier which is administered or disposed in the vitreous. A therapeutic agent for ophthalmic diseases comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. 8. The agent according to item 7 of the patent scope of claim 4, wherein the above-mentioned compound (four), fiuvastatin, i-tatin or cerivastatin is ι or more. 312XP/Inventive Manual (Supplement)/97-01/96138443 71 200824682 9. In the eyes of the seventh paragraph of the patent application, the above-mentioned fat, 容#步,查,丁丁. Day/Deep Stade is a simvastatin with either or both of β 〇. And nuvastatin ι〇·If you apply for the 8th or 9th dose of the patent, you will enter it into (4) (4). Treatment of m disease 11. An ophthalmic agent as claimed in claim 8 or 9 which has a sustained release carrier which is administered or placed in the eye. ', 'C' / Q treatment 卞 / W * Please (4) _ 8 or 9 of the treatment of ophthalmic diseases Μ 'There are sustained release carriers for administration or placement in the vitreous. ', 13. A neovascular inhibitor in the eye which contains a liposoluble, a pharmaceutically acceptable salt thereof, or a pharmaceutical thereof as an active ingredient. + 谷谷之洛剂化合物 / 14. As claimed in the scope of the application of the substance μ, wherein the above-mentioned fat-soluble Stella, D: the official inhibition of I fine, combined more illegal / Ding simvastatin, nuvastatin, lovastatin or There are two or more types of cerivastatin. 15. The intraocular neonatal angiogenesis agent according to claim 13, wherein the fat-soluble Statin is any one or both of simvastatin and fluvastatin. 16. For example, a neovascular inhibitor in the eye of claim 14 or 5 is administered intraocularly. 17. A neovascular inhibitor in the eye as claimed in claim 14 or 15 which has a sustained release carrier which is administered or disposed in the eye. 18. The preparation of the neovascularization 312XP/invention specification (supplement)/97-01/96138443 72 200824682 in the eye of claim 14 or 15 of the patent application, which has a sustained release load administered or placed in the vitreous body. 19. A fresh blood dry preparation in the eye of claim 14 or 15 for inhibiting the production of new blood vessels from the retina. The cell proliferation inhibitor or the cell contraction inhibitor in the eye contains a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. 21. The cell-stimulating or cytostatic agent in the eye of claim 2, wherein any of the above-mentioned fat-soluble statins simvastatin, fluvastatin, 1〇ν&_ΐίη or cerivastatin or 2 More than one species. 22. The cell proliferation inhibitor or cell contraction inhibitor of the eye of claim 2G, wherein any one or both of the above-mentioned fat-soluble Statin is simvastatin and fluvastatin. ', 23. A cell proliferation inhibitor or cell contraction inhibitor in the eye of claim 21 or 22, wherein it is administered intraocularly. 24. A cell proliferation inhibitor or cell contraction inhibitor in the eye of claim 21 or 22 which has a sustained release carrier which is administered or disposed in the eye. 25. A cell proliferation inhibitor or cell contraction inhibitor' in the eye of claim 21 or 22 which has a sustained release carrier which is administered or disposed in the vitreous. 26. A cell proliferation inhibitor of the replication eye or a cell contraction inhibitor of the replication eye, which comprises a fat-soluble history, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. 312XP/Inventive Manual (Supplement)/97·〇ι/96138443 200824682 27. A cell proliferation inhibitory agent, or a replication cell cytoskeletal inhibitor, of the replication eye of claim 26, wherein the above fat soluble history ' / Ding simvastatin, fluvastatin, lovastatin, or "cerivastatin, any one or more. 28. For example, the cell proliferation inhibitor of the replication eye or the cell contraction inhibitor of the replication eye of claim 27, wherein Any one or both of the above-mentioned fat-soluble Stella > Dings simvastatin and fiuvastatin. 29. The cell proliferation inhibitor of the replication eye or the cell contraction inhibitor of the replication eye as claimed in claim 27 or 28, Wherein, it is administered intraocularly. 30. The cell proliferation inhibitor of the replication eye or the cell contraction inhibitor of the replication eye of claim 27 or 28, which has a sustained release administered or placed in the eye. a carrier for the replication of the eye, or a cell contraction inhibitor of the replication eye, as claimed in claim 27 or 28 Or a sustained release carrier provided in the vitreous. 32. A therapeutic or prophylactic agent for exudative age-related macular degeneration comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable substance thereof The granules are used as an active ingredient. • 3 3 · The therapeutic or prophylactic agent for exudative age-related macular degeneration according to item 32 of the patent scope, wherein the above-mentioned fat-soluble statin simvastatin, fluvastatin, Any one or more of lovastatin or cerivastatin. 312XP/Invention Manual (supplement)/97-01/96138443 74 200824682 34. Treatment or prevention of exudative age-related macular degeneration as claimed in claim 32 And a therapeutic agent or a prophylactic agent for exudative age-related macular degeneration according to claim 33 or 34, wherein Intraocular administration. 36. A therapeutic or prophylactic agent for exudative age-related macular degeneration according to claim 33 or 34, which has been administered or disposed of A therapeutic or prophylactic agent for exudative age-related macular degeneration according to claim 33 or 34, which has a sustained-release carrier which is administered or placed in a vitreous body. A therapeutic or prophylactic agent for atrophic age-related macular degeneration comprising a fat-soluble statin, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as an active ingredient. 39. The therapeutic or prophylactic agent for atrophic age-related macular degeneration according to claim 38, wherein the fat-soluble Statin is any one or more of simvastatin, fluvastatin, lovastatin or cerivastatin. 40. The therapeutic or prophylactic agent for atrophic age-related macular degeneration according to claim 38, wherein the fat-soluble statin is any one or both of simvastatin and fluvastatin. 41. A therapeutic or prophylactic agent for atrophic age-related macular degeneration according to claim 39 or 40 of the patent application, wherein it is administered intraocularly. 42. Atrophic senile macular 312 χ ρ 发明 发明 发明 发明 发明 发明 发明 发明 97 97 97 97 97 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 Investing carrier. / 43. A therapeutic or pre-treatment agent for atrophic age-related macular degeneration according to claim 39 or 4, which has a sustained release carrier or a sustained release carrier. 44. A therapeutic or prophylactic agent for diabetic retinopathy, 51 retinal detachment, vitreous hemorrhage, macular edema or retinopathy of prematurity, containing fat-soluble money, a chemically acceptable salt or a pharmaceutically acceptable solvent thereof The compound acts as an active ingredient. 45. A therapeutic or prophylactic agent for diabetic retinopathy, traction=retinal dissection, vitreous hemorrhage, macular edema or retinopathy of prematurity according to claim 44, wherein the above-mentioned fat-soluble statin is simvastatin^fluvastatin>lovastatincerivastatin Any one or two or more types. 46. A therapeutic or prophylactic agent for diabetic retinopathy, traction retinal detachment, vitreous sputum, macular edema or retinopathy of prematurity, according to the 44th scope of the patent application, wherein any of the above-mentioned fat-soluble statins are simvastatin and fiuvastatin One or both. (4) 47. A therapeutic or prophylactic agent for diabetic retinopathy, or traction retinal detachment, vitreous hemorrhage, macular edema or retinopathy of prematurity as claimed in claim 45 or 46, wherein it is administered intraocularly. 48. A therapeutic or prophylactic agent for diabetic retinopathy and traction retinal detachment, vitreous hemorrhage, macular edema or retinopathy of prematurity as claimed in claim 45 or 46, which has been administered or placed in the eye 312XP/invention Instructions (supplement) / 97-01/9613 8443 76 200824682 sustained release carrier. 49. A therapeutic or prophylactic agent for diabetic retinopathy, traction retinal detachment, vitreous hemorrhage, macular edema or retinopathy of prematurity in claim 45 or 46, which has sustained release property administered or placed in the vitreous Carrier. A therapeutic agent for uveitis, allergic conjunctivitis, or spring conjunctivitis, which contains a fat-soluble statin, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. 51. The therapeutic agent for uveitis, allergic conjunctivitis or spring conjunctivitis according to the fifth aspect of the invention, wherein the fat-soluble Statin is one or more selected from the group consisting of simvastatin, fluvastatin, lovastatin or cerivastatin. 52. The therapeutic agent for uveitis, allergic conjunctivitis or spring conjunctivitis according to the fifth aspect of the patent application, wherein the fat-soluble Statin is any one or both of simvastatin and fluvastatin. • 53. A therapeutic agent for uveitis, allergic conjunctivitis or spring conjunctivitis as claimed in claim 51 or 52, wherein it is administered intraocularly. 54. A therapeutic agent for uveitis, allergic conjunctivitis or spring conjunctivitis according to claim 51 or 52, which has a sustained release carrier for administration or placement in the eye. A sustained-release carrier in the body containing a fat-soluble sulphate of a therapeutic or prophylactic agent for glaucoma 312XP/invention specification (supplement)/97-01/96138443 77 200824682 > Ding, Qi Le Xueshang The permissible salt or a pharmaceutically acceptable solvate thereof is used as an active ingredient. 57. For example, the therapeutic agent or prophylaxis of Qingchun, the first part of the scope of patents, may be any of the above-mentioned fat-soluble statins simvas1:atin, f luvastatin lovastatin or cerivastatin. 58. The therapeutic or prophylactic agent for #光光 according to claim 56, wherein the fat-soluble Statin is any one or both of simvastatin and fluvastatin. 59. A therapeutic or prophylactic agent for glaucoma according to claim 57 or 58 in which the intraocular administration is administered. 60. A therapeutic or prophylactic agent for glaucoma according to claim 57 or 58 of the patent application having a sustained release carrier for administration or placement in the eye. 61. A therapeutic or prophylactic agent for glaucoma according to claim 57 or 58 which has a sustained release carrier which is administered or placed in a vitreous. A therapeutic or prophylactic agent for proliferative vitreoretinopathy, which comprises a fat-soluble statin, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof as an active ingredient. And a therapeutic or prophylactic agent for proliferative vitreoretinopathy according to the 62nd aspect of the invention, wherein the fat-soluble statin is one or more selected from the group consisting of simvastatin, fiuvastatin, 〇vastatin or cerivastatin. 64. A therapeutic or prophylactic agent for proliferative vitreoretinopathy according to claim 62, wherein the above-mentioned fat-soluble Statin system 312XP/invention specification (supplement)/97-01/96138443 78 200824682 simvastatin and f丨uvastatin Either or both of them. 65. The proliferative vitreous optic network according to claim 63 or 64, wherein the therapeutic or prophylactic agent for the membranous lesion is administered intraocularly. 66. A therapeutic or prophylactic agent for proliferative vitreous reticulum lesions according to claim 63 or 64, which has a sustained release carrier for administration or placement in the eye. A therapeutic or prophylactic agent for a proliferative vitreous optic menteuropathy according to claim 63 or 64, which comprises a sustained release carrier administered or placed in a vitreous. 312XP/Invention Manual) /97-01/96138443